Treatment Research

In a clinical trial, people being treated for cancer who participated in virtual mind–body fitness classes were less likely to be hospitalized, and had shorter stays when they were hospitalized, than people who did not take the classes.

NCI’s James H. Doroshow, M.D., reflects on the accomplishments of NCI-MATCH, a first-of-its-kind precision medicine cancer trial, and gives an overview of three new successor trials: ComboMATCH, MyeloMATCH, and iMATCH.

A new study, conducted largely in mice, may help explain why a currently used molecular marker—called mismatch repair deficiency—doesn’t always work to predict which patients will respond to immunotherapies called immune checkpoint inhibitors.

New approach may increase the effectiveness of T-cell-based immunotherapy treatments against solid tumors.

A cancer-infecting virus engineered to tamp down a tumor’s ability to suppress the immune system shrank tumors in mice, a new study shows. The modified oncolytic virus worked even better when used along with an immune checkpoint inhibitor.

Despite recommendations, a new analysis shows few people with cancer undergo germline testing to learn if their cancer may have been caused by gene changes inherited from a parent. Germline testing can help doctors determine the best treatments for a patient and help identify people whose family members may be at higher risk of cancer.

ComboMATCH will consist of numerous phase 2 cancer treatment trials that aim to identify promising drug combinations that can advance to larger, more definitive clinical trials.

A new study has compared three formulations of an mRNA vaccine designed to treat cancers caused by human papillomavirus (HPV) infections. All three vaccines showed promise in mice.

Researchers have identified a mechanism by which cancer cells develop specific genetic changes needed to become resistant to targeted therapies. They also showed that this process, called non-homologous end-joining (NHEJ), can potentially be disrupted.

For some people with cancer, is 6 months of immunotherapy the only treatment they might ever need? Or 4 weeks of immunotherapy followed by minor surgery? Results from several small clinical trials suggest these scenarios may be bona fide possibilities.

Two research teams have developed ways of overcoming barriers that have limited the effectiveness of CAR T-cell therapies, including engineering ways to potentially make them effective against solid tumors like pancreatic cancer and melanoma.

In people with cancer treated with immune checkpoint inhibitors, a rare, but often fatal, side effect is inflammation in the heart, called myocarditis. Researchers have now identified a potential chief cause of this problem: T cells attacking a protein in heart cells called α-myosin.

Researchers have modified a chemo drug, once abandoned because it caused serious gut side effects, so that it is only triggered in tumors but not normal tissues. After promising results in mice, the drug, DRP-104, is now being tested in a clinical trial.

Two research teams have developed a treatment approach that could potentially enable KRAS-targeted drugs—and perhaps other targeted cancer drugs—flag cancer cells for the immune system. In lab studies, the teams paired these targeted drugs with experimental antibody drugs that helped the immune system mount an attack.

Inflammation is considered a hallmark of cancer. Researchers hope to learn more about whether people with cancer might benefit from treatments that target inflammation around tumors. Some early studies have yielded promising results and more are on the horizon.

NCI researchers are developing an immunotherapy that involves injecting protein bits from cytomegalovirus (CMV) into tumors. The proteins coat the tumor, causing immune cells to attack. In mice, the treatment shrank tumors and kept them from returning.

FDA has approved the combination of the targeted drugs dabrafenib (Tafinlar) and trametinib (Mekinist) for nearly any type of advanced solid tumor with a specific mutation in the BRAF gene. Data from the NCI-MATCH trial informed the approval.

People with cancer who take immunotherapy drugs often develop skin side effects, including itching and painful rashes. New research in mice suggests these side effects may be caused by the immune system attacking new bacterial colonies on the skin.

Researchers have developed tiny “drug factories” that produce an immune-boosting molecule and can be implanted near tumors. The pinhead-sized beads eliminated tumors in mice with ovarian and colorectal cancer and will soon be tested in human studies.

Women are more likely than men to experience severe side effects from cancer treatments such as chemotherapy, targeted therapy, and immunotherapy, a new study finds. Researchers hope the findings will increase awareness of the problem and help guide patient care.

Research to improve CAR T-cell therapy is progressing rapidly. Researchers are working to expand its use to treat more types of cancer and better understand and manage its side effects. Learn how CAR T-cell therapy works, which cancers it’s used to treat, and current research efforts.

Experts say studies are needed on how to best transition telehealth from a temporary solution during the pandemic to a permanent part of cancer care that’s accessible to all who need it.

Removing immune cells called naive T cells from donated stem cells before they are transplanted may prevent chronic graft-versus-host disease (GVHD) in people with leukemia, a new study reports. The procedure did not appear to increase the likelihood of patients’ cancer returning.

A specific form of the HLA gene, HLA-A*03, may make immune checkpoint inhibitors less effective for some people with cancer, according to an NCI-led study. If additional studies confirm the finding, it could help guide the use of these commonly used drugs.

The success of mRNA vaccines for COVID-19 could help accelerate research on using mRNA vaccine technology to treat cancer, including the development of personalized cancer vaccines.

Aneuploidy—when cells have too many or too few chromosomes—is common in cancer cells, but scientists didn’t know why. Two new studies suggest that aneuploidy helps the cells survive treatments like chemotherapy and targeted therapies.

New research suggests that fungi in the gut may affect how tumors respond to cancer treatments. In mice, when bacteria were eliminated with antibiotics, fungi filled the void and impaired the immune response after radiation therapy, the study found.

FDA has approved belumosudil (Rezurock) for the treatment of chronic graft-versus-host disease (GVHD). The approval covers the use of belumosudil for people 12 years and older who have already tried at least two other therapies.

In lab studies, the antibiotic novobiocin showed promise as a treatment for cancers that have become resistant to PARP inhibitors. The drug, which inhibits a protein called DNA polymerase theta, will be tested in NCI-supported clinical trials.

A drug called avasopasem manganese, which has been found to protect normal tissues from radiation therapy, can also make cancer cells more vulnerable to radiation treatment, a new study in mice suggests.

While doctors are familiar with the short-term side effects of immune checkpoint inhibitors, less is known about potential long-term side effects. A new study details the chronic side effects of these drugs in people who received them as part of treatment for melanoma.

Cholesterol-lowering drugs known as PCSK9 inhibitors may improve the effectiveness of cancer immune checkpoint inhibitors, according to studies in mice. The drugs appear to improve the immunotherapy drugs’ ability to find tumors and slow their growth.

Researchers have developed a nanoparticle that trains immune cells to attack cancer. According to the NCI-funded study, the nanoparticle slowed the growth of melanoma in mice and was more effective when combined with an immune checkpoint inhibitor.

A comprehensive analysis of patients with cancer who had exceptional responses to therapy has revealed molecular changes in the patients’ tumors that may explain some of the exceptional responses.

Researchers are developing a new class of cancer drugs called radiopharmaceuticals, which deliver radiation therapy directly and specifically to cancer cells. This Cancer Currents story explores the research on these emerging therapies.

FDA has recently approved two blood tests, known as liquid biopsies, that gather genetic information to help inform treatment decisions for people with cancer. This Cancer Currents story explores how the tests are used and who can get the tests.

Cancer cells with a genetic feature called microsatellite instability-high (MSI-high) depend on the enzyme WRN to survive. A new NCI study explains why and reinforces the idea of targeting WRN as a treatment approach for MSI-high cancer.

Efforts to contain the opioid epidemic may be preventing people with cancer from receiving appropriate prescriptions for opioids to manage their cancer pain, according to a new study of oncologists’ opioid prescribing patterns.

The gene-editing tool CRISPR is changing the way scientists study cancer, and may change how cancer is treated. This in-depth blog post describes how this revolutionary technology is being used to better understand cancer and create new treatments.

FDA’s approval of pembrolizumab (Keytruda) to treat people whose cancer is tumor mutational burden-high highlights the importance of genomic testing to guide treatment, including for children with cancer, according to NCI Director Dr. Ned Sharpless.

Patients with acute graft-versus-host disease (GVHD) that does not respond to steroid therapy are more likely to respond to the drug ruxolitinib (Jakafi) than other available treatments, results from a large clinical trial show.

NCI is developing the capability to produce cellular therapies, like CAR T cells, to be tested in cancer clinical trials at multiple hospital sites. Few laboratories and centers have the capability to make CAR T cells, which has limited the ability to test them more broadly.

An experimental drug may help prevent the chemotherapy drug doxorubicin from harming the heart and does so without interfering with doxorubicin’s ability to kill cancer cells, according to a study in mice.

In people with blood cancers, the health of their gut microbiome appears to affect the risk of dying after receiving an allogeneic hematopoietic stem cell transplant, according to an NCI-funded study conducted at four hospitals across the globe.

A novel approach to analyzing tumors may bring precision cancer medicine to more patients. A study showed the approach, which analyzes gene expression using tumor RNA, could accurately predict whether patients had responded to treatment with targeted therapy or immunotherapy.

Bone loss associated with chemotherapy appears to be induced by cells that stop dividing but do not die, a recent study in mice suggests. The researchers tested drugs that could block signals from these senescent cells and reverse bone loss in mice.

Some experts believe that proton therapy is safer than traditional radiation, but research has been limited. A new observational study compared the safety and effectiveness of proton therapy and traditional radiation in adults with advanced cancer.

In people with cancer, the abscopal effect occurs when radiation—or another type of localized therapy—shrinks a targeted tumor but also causes untreated tumors in the body to shrink. Researchers are trying to better understand this phenomenon and take advantage of it to improve cancer therapy.

An experimental drug, AMG 510, that targets mutated forms of the KRAS protein completely shrank tumors in cancer mouse models and data from a small clinical trial show that it appears to be active against different cancer types with a KRAS mutation.

Researchers have engineered an oncolytic virus to kill cancer cells and boost the immune response against tumors. In a new study, the virus provided T cells around tumors with a hormone they need for their own cell-killing functions.

FDA has approved entrectinib (Rozlytrek) for the treatment of children and adults with tumors bearing an NTRK gene fusion. The approval also covers adults with non-small cell lung cancer harboring a ROS1 gene fusion.

A new NCI-supported study showed that altering cancer cell metabolism by feeding mice a diet very low in the nutrient methionine improved the ability of chemotherapy and radiation therapy to shrink tumors.

An NCI-funded clinical trial is testing the immunotherapy drug nivolumab (Opdivo) in people who have advanced cancer and an autoimmune disease, such as rheumatoid arthritis, lupus, or multiple sclerosis, who are often excluded from such trials.

Researchers have identified a protein called CD24 that may be a new target for cancer immunotherapy. The protein is a ‘don’t eat me’ signal that prevents immune cells called macrophages from engulfing and eating cells.

Injecting cells undergoing necroptosis, a form of cell death, into tumors in mice kickstarted an immune response against the tumors, researchers have found. When combined with immunotherapy, the treatment was effective at eliminating tumors in mice.

Researchers have identified proteins that may play a central role in transforming T cells from powerful destroyers to depleted bystanders that can no longer harm cancer cells. The findings could lead to strategies for boosting cancer immunotherapies.

Did you know that NCI supports clinical trials of new treatments for pet dogs with cancer? Learn more about NCI’s comparative oncology studies and how they may also help people with cancer.

Researchers have discovered a potential way to turn on one of the most commonly silenced tumor-suppressor proteins in cancer, called PTEN. They also found a natural compound, I3C, that in lab studies could flip the on switch.

New findings from a clinical trial suggest that a single dose of radiation therapy may control painful bone metastases as effectively as multiple lower doses of radiation therapy.

The expanding use of cancer immunotherapy has revealed a variety of side effects associated with this treatment approach. Researchers are now trying to better understand how and why these side effects occur and develop strategies for better managing them.

The investigational immunotherapy drug bintrafusp alfa (also called M7824), a bifunctional fusion protein, shrank the tumors of some patients with advanced HPV-related cancers, according to results from a phase 1 clinical trial.

A new study provides insight into how cancer immunotherapy works and suggests ways to enhance the treatment’s effectiveness. The NCI-led study, published in Science, examined the effect of high potassium levels on T cells.

Pain is a common and much-feared symptom among people with cancer and long-term survivors. As more people survive cancer for longer periods, there is a renewed interest in developing new, nonaddictive approaches for managing their chronic pain.

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What Is Cancer?

  • PMID: 31761807
  • DOI: 10.1353/pbm.2019.0046

This essay focuses on themes in Explaining Cancer: Finding Order in Disorder (2018) by Anya Plutynski, a monograph that has important things to say about both the peculiarities of cancers and our theories about them. Cancer's agents of destruction are human cells that have been recruited and to some extent transformed into pathological organisms or the building blocks of tumors. Cancers both undermine and exploit mechanisms of multicellular organization, and understanding them gives rise to difficult philosophical problems. In addition to sketching Plutynski's discussion of these problems, this essay defends Christopher Boorse's account of disease from Plutynski's criticisms, and it expresses some qualms about her treatment of scientific explanation.

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Page 1 of 107

Identification of CD160-TM as a tumor target on triple negative breast cancers: possible therapeutic applications

Despite major therapeutic advances, triple-negative breast cancer (TNBC) still presents a worth prognosis than hormone receptors-positive breast cancers. One major issue relies in the molecular and mutational ...

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Contrast-enhanced ultrasound to predict malignant upgrading of atypical ductal hyperplasia

A malignancy might be found at surgery in cases of atypical ductal hyperplasia (ADH) diagnosed via US-guided core needle biopsy (CNB). The objective of this study was to investigate the diagnostic performance ...

MRI-based tumor shrinkage patterns after early neoadjuvant therapy in breast cancer: correlation with molecular subtypes and pathological response after therapy

MRI-based tumor shrinkage patterns (TSP) after neoadjuvant therapy (NAT) have been associated with pathological response. However, the understanding of TSP after early NAT remains limited. We aimed to analyze ...

Are better AI algorithms for breast cancer detection also better at predicting risk? A paired case–control study

There is increasing evidence that artificial intelligence (AI) breast cancer risk evaluation tools using digital mammograms are highly informative for 1–6 years following a negative screening examination. We h...

Prognostic impact of HER2 biomarker levels in trastuzumab-treated early HER2-positive breast cancer

Overexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual sco...

The novel phosphatase NUDT5 is a critical regulator of triple-negative breast cancer growth

The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the h...

Low-dose acetylsalicylic acid reduces local inflammation and tissue perfusion in dense breast tissue in postmenopausal women

One major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to ~ 30% of all breast cancer. Prevention targeting dense breast tissue has the ...

Improving lesion detection in mammograms by leveraging a Cycle-GAN-based lesion remover

The wide heterogeneity in the appearance of breast lesions and normal breast structures can confuse computerized detection algorithms. Our purpose was therefore to develop a Lesion Highlighter (LH) that can impro...

TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer

Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. ...

ADAMTS18 deficiency associates extracellular matrix dysfunction with a higher risk of HER2-positive mammary tumorigenesis and metastasis

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for about 20% of all breast cancer cases and is correlated with a high relapse rate and poor prognosis. ADAMTS18 is proposed as an i...

Development of a machine learning-based radiomics signature for estimating breast cancer TME phenotypes and predicting anti-PD-1/PD-L1 immunotherapy response

Since breast cancer patients respond diversely to immunotherapy, there is an urgent need to explore novel biomarkers to precisely predict clinical responses and enhance therapeutic efficacy. The purpose of our...

Development and prognostic validation of a three-level NHG-like deep learning-based model for histological grading of breast cancer

Histological grade is a well-known prognostic factor that is routinely assessed in breast tumours. However, manual assessment of Nottingham Histological Grade (NHG) has high inter-assessor and inter-laboratory...

A genome-wide association study of contralateral breast cancer in the Women’s Environmental Cancer and Radiation Epidemiology Study

Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common ...

Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea

The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a d...

Increased risk of contralateral breast cancer for BRCA1/2 wild-type, high-risk Korean breast cancer patients: a retrospective cohort study

This study aimed to investigate the contralateral breast cancer (CBC) recurrence rate in Korean breast cancer patients according to their BRCA1/2 germline mutation status, focusing particularly on the CBC recurre...

c-MET-positive circulating tumor cells and cell-free DNA as independent prognostic factors in hormone receptor-positive/HER2-negative metastatic breast cancer

Endocrine therapy resistance in hormone receptor-positive/HER2-negative (HR+/HER2−) breast cancer (BC) is a significant clinical challenge that poses several unmet needs in the management of the disease. This ...

Digital image analysis and machine learning-assisted prediction of neoadjuvant chemotherapy response in triple-negative breast cancer

Pathological complete response (pCR) is associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, only 30–40% of TNBC patients treated with neoadjuvant chemotherapy (N...

Evidence of steady-state fibroblast subtypes in the normal human breast as cells-of-origin for perturbed-state fibroblasts in breast cancer

Human breast cancer most frequently originates within a well-defined anatomical structure referred to as the terminal duct lobular unit (TDLU). This structure is endowed with its very own lobular fibroblasts r...

PFKP deubiquitination and stabilization by USP5 activate aerobic glycolysis to promote triple-negative breast cancer progression

Triple-negative breast cancer (TNBC) remains the most challenging subtype of breast cancer and lacks definite treatment targets. Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to ...

Prognostic value of baseline neutrophil/lymphocyte ratio in HER2-positive metastatic breast cancer: exploratory analysis of data from the CLEOPATRA trial

This study aimed to evaluate the prognostic role of the baseline neutrophil/lymphocyte ratio (NLR) in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab/pertuzumab.

Risk-management decision-making data from a community-based sample of racially diverse women at high risk of breast cancer: rationale, methods, and sample characteristics of the Daughter Sister Mother Project survey

To understand the dynamics that limit use of risk-management options by women at high risk of breast cancer, there is a critical need for research that focuses on patient perspectives. Prior research has left ...

Machine learning prediction of pathological complete response and overall survival of breast cancer patients in an underserved inner-city population

Generalizability of predictive models for pathological complete response (pCR) and overall survival (OS) in breast cancer patients requires diverse datasets. This study employed four machine learning models to...

Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant

Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.

Targeting tumor–stromal interactions in triple-negative breast cancer using a human vascularized micro-tumor model

Triple-negative breast cancer (TNBC) is highly aggressive with limited available treatments. Stromal cells in the tumor microenvironment (TME) are crucial in TNBC progression; however, understanding the molecu...

Identification of a Notch transcriptomic signature for breast cancer

Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therap...

A prospective study on tumour response assessment methods after neoadjuvant endocrine therapy in early oestrogen receptor-positive breast cancer

Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecul...

Addition of polygenic risk score to a risk calculator for prediction of breast cancer in US Black women

Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory perform...

Protein disulfide isomerase family member 4 promotes triple-negative breast cancer tumorigenesis and radiotherapy resistance through JNK pathway

Despite radiotherapy ability to significantly improve treatment outcomes and survival in triple-negative breast cancer (TNBC) patients, acquired resistance to radiotherapy poses a serious clinical challenge. P...

Association between allostatic load and breast cancer risk: a cohort study

Allostatic load (AL) reflects the collective load of chronic stress during lifetime. Previous studies have shown that higher AL is associated with poor clinical outcomes among breast cancer patients. However, ...

HER2 amplification level by in situ hybridization predicts survival outcome in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 IHC results

The role of HER2 amplification level in predicting the effectiveness of HER2-directed therapies has been established. However, its association with survival outcomes in advanced HER2-positive breast cancer tre...

Effect of histological breast cancer subtypes invasive lobular versus non-special type on survival in early intermediate-to-high-risk breast carcinoma: results from the SUCCESS trials

Invasive lobular breast carcinomas (ILC) have different histological features compared to non-special type carcinomas (NST), but the effect of histological subtypes on survival is controversial. In this study,...

Prevalence of BRCA1 , BRCA2 , and PALB2 genomic alterations among 924 Taiwanese breast cancer assays with tumor-only targeted sequencing: extended data analysis from the VGH-TAYLOR study

The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significa...

Therapeutic protein PAK restrains the progression of triple negative breast cancer through degrading SREBP-1 mRNA

Triple-negative breast cancer (TNBC) represents the most challenging subtype of breast cancer. Studies have implicated an upregulation of lipid synthesis pathways in the initiation and progression of TNBC. Tar...

Mosquito control exposures and breast cancer risk: analysis of 1071 cases and 2096 controls from the Ghana Breast Health Study

Epidemiologic data on insecticide exposures and breast cancer risk are inconclusive and mostly from high-income countries. Using data from 1071 invasive pathologically confirmed breast cancer cases and 2096 co...

Molecular subtypes of breast cancer predicting clinical benefits of radiotherapy after breast-conserving surgery: a propensity-score-matched cohort study

Based on the molecular expression of cancer cells, molecular subtypes of breast cancer have been applied to classify patients for predicting clinical outcomes and prognosis. However, further evidence is needed...

Key regulator PNPLA8 drives phospholipid reprogramming induced proliferation and migration in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and leads to the poorest patient outcomes despite surgery and chemotherapy treatment. Exploring new molecular mechanisms of TNB...

Development and evaluation of a method to assess breast cancer risk using a longitudinal history of mammographic density: a cohort study

Women with dense breasts have an increased risk of breast cancer. However, breast density is measured with variability, which may reduce the reliability and accuracy of its association with breast cancer risk....

Histologic tumor type as a determinant of survival in hormone receptor-positive, HER2-negative, pT1-3 invasive ductal and lobular breast cancer

The aim of the study was to compare the difference in survival between invasive ductal (IDC) and lobular carcinoma (ILC).

Integrative whole-genome and transcriptome analysis of HER2-amplified metastatic breast cancer

In breast cancer, the advent of anti-HER2 therapies has made HER2+ tumors a highly relevant subgroup. However, the exact characteristics which prohibit clinical response to anti-HER2 therapies and drive diseas...

The BET degrader ZBC260 suppresses stemness and tumorigenesis and promotes differentiation in triple-negative breast cancer by disrupting inflammatory signaling

Breast cancer stem cells (BCSCs) are resistant to standard therapies, facilitate tumor dissemination, and contribute to relapse and progression. Super-enhancers are regulators of stemness, and BET proteins, wh...

Formation of an invasion-permissive matrix requires TGFβ/SNAIL1-regulated alternative splicing of fibronectin

As in most solid cancers, the emergence of cells with oncogenic mutations in the mammary epithelium alters the tissue homeostasis. Some soluble factors, such as TGFβ, potently modify the behavior of healthy st...

PROACTING: predicting pathological complete response to neoadjuvant chemotherapy in breast cancer from routine diagnostic histopathology biopsies with deep learning

Invasive breast cancer patients are increasingly being treated with neoadjuvant chemotherapy; however, only a fraction of the patients respond to it completely. To prevent overtreatment, there is an urgent nee...

AMEERA-4: a randomized, preoperative window-of-opportunity study of amcenestrant versus letrozole in early breast cancer

Window-of-opportunity (WOO) studies provide insights into the clinical activity of new drugs in breast cancer.

Blocking channels to metastasis: targeting sodium transport in breast cancer

The development of therapies that can suppress invasion and prevent metastasis, ‘anti-metastatic drugs’, is an important area of unmet therapeutic need. The new results of a recent open-label, multicentre rand...

High inter-laboratory variability in the assessment of HER2-low breast cancer: a national registry study on 50,714 Danish patients

Considering the recent advancements in the treatment of breast cancer with low expression of human epidermal growth factor receptor 2 (HER2), we aimed to examine inter-laboratory variability in the assessment ...

Multimodal prediction of neoadjuvant treatment outcome by serial FDG PET and MRI in women with locally advanced breast cancer

To investigate combined MRI and 18 F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer.

A catchment and location-allocation analysis of mammography access in Delaware, US: implications for disparities in geographic access to breast cancer screening

Despite a 40% reduction in breast cancer mortality over the last 30 years, not all groups have benefited equally from these gains. A consistent link between later stage of diagnosis and disparities in breast c...

Alterations to DNA methylation patterns induced by chemotherapy treatment are associated with negative impacts on the olfactory pathway

Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients.

Exploring the interface zone in breast cancer: implications for surgical strategies and beyond

The prognostic value of a combined immune score in tumor and immune cells assessed by immunohistochemistry in triple-negative breast cancer.

This study aimed to develop a novel combined immune score (CIS)-based model assessing prognosis in triple-negative breast cancer (TNBC).

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Breast Cancer Research

ISSN: 1465-542X

ScienceDaily

Researchers characterize the immune landscape in cancer

Findings could pave the way for the development of new therapeutic strategies.

Researchers from the Icahn School of Medicine at Mount Sinai, in collaboration with the Clinical Proteomic Tumor Analysis Consortium of the National Institutes of Health, The University of Texas MD Anderson Cancer Center, Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and others, have unveiled a detailed understanding of immune responses in cancer, marking a significant development in the field. The findings were published in the February 14 online issue of Cell .

Utilizing data from more than 1,000 tumors across 10 different cancers, the study is the first to integrate DNA, RNA, and proteomics (the study of proteins), revealing the complex interplay of immune cells in tumors. The data came from the Clinical Proteomic Tumor Analysis Consortium (CPTAC), a program under the National Cancer Institute.

"We aimed to improve our understanding of the mechanisms underlying the functional impairment of immune response in tumors. By closely examining genes and proteins in the tumor tissues, we discovered various patterns in immune activation and suppression," says Pei Wang, PhD, Professor of Genetics and Genomic Sciences at Icahn Mount Sinai, and the lead-corresponding author on the paper. "Our goal in unraveling these diverse immune subtypes is to help clinicians identify patient groups more responsive to immunotherapy. Revealing the specific pathways and cellular switches for each subtype can also spark new and creative ways to develop treatments."

"Each type of immune response was linked to changes in gene functions, such as how genes are modified, the messages they send, and the proteins they produce. By providing a comprehensive molecular fingerprint of the immune response in cancer, this study is expected to facilitate the development of future immunotherapy strategies," says Francesca Petralia, PhD, Assistant Professor of Genetics and Genomic Sciences at Icahn Mount Sinai, and co-corresponding author on the paper.

A key finding was that among seven subtypes identified through advanced statistical models, five included tumors from ten different types of cancer, suggesting shared immune responses across these tumors.

"When we see common immune responses and similar patterns in the way cells behave across various cancers within the same immune group, it hints that certain treatments that boost the immune system could work well for many types of cancer," says Dr. Wang.

A novel aspect of the research stems from the deep phosphoproteomic data generated for more than 1,000 tumors. This data allows researchers to see how proteins are modified. "With phosphoproteomic profiling of more than 1,000 pan-cancer tumors, we were able to computationally discover a set of key novel drug targets," says Avi Ma'ayan, PhD, Professor, Pharmacological Sciences, Director of the Mount Sinai Center for Bioinformatics at Icahn Mount Sinai, and a senior author of the paper. "By targeting selected kinases with small molecules or other means, we may be able to convert tumors not responding to immunotherapies into tumors with better immune-therapy response."

As part of the research, a machine-learning tool applied to digital pathology images also demonstrated correlations between different types of immune responses and the presence of certain immune cells, enhancing understanding of the environment in and around tumors.

Next, the investigators plan to validate their findings further and leverage insights in ongoing clinical studies focused on immunotherapies. This effort aims to streamline the development of biomarker panels for treatment responses and identify enhanced treatment strategies. Collaborative efforts within CPTAC are underway, including a proteogenomic study on molecular mechanisms underlying responses to immune checkpoint treatments in melanoma patients.

  • Immune System
  • Brain Tumor
  • Lung Cancer
  • Skin Cancer
  • Prostate Cancer
  • Ovarian Cancer
  • Molecular biology
  • Immune system
  • White blood cell
  • Monoclonal antibody therapy
  • Chemotherapy

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Materials provided by The Mount Sinai Hospital / Mount Sinai School of Medicine . Note: Content may be edited for style and length.

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  • Francesca Petralia, Weiping Ma, Tomer M. Yaron, Francesca Pia Caruso, Nicole Tignor, Joshua M. Wang, Daniel Charytonowicz, Jared L. Johnson, Emily M. Huntsman, Giacomo B. Marino, Anna Calinawan, John Erol Evangelista, Myvizhi Esai Selvan, Shrabanti Chowdhury, Dmitry Rykunov, Azra Krek, Xiaoyu Song, Berk Turhan, Karen E. Christianson, David A. Lewis, Eden Z. Deng, Daniel J.B. Clarke, Jeffrey R. Whiteaker, Jacob J. Kennedy, Lei Zhao, Rossana Lazcano Segura, Harsh Batra, Maria Gabriela Raso, Edwin Roger Parra, Rama Soundararajan, Ximing Tang, Yize Li, Xinpei Yi, Shankha Satpathy, Ying Wang, Maciej Wiznerowicz, Tania J. González-Robles, Antonio Iavarone, Sara J.C. Gosline, Boris Reva, Ana I. Robles, Alexey I. Nesvizhskii, D.R. Mani, Michael A. Gillette, Robert J. Klein, Marcin Cieslik, Bing Zhang, Amanda G. Paulovich, Robert Sebra, Zeynep H. Gümüş, Galen Hostetter, David Fenyö, Gilbert S. Omenn, Lewis C. Cantley, Avi Ma'ayan, Alexander J. Lazar, Michele Ceccarelli, Pei Wang, Jennifer Abelin, François Aguet, Yo Akiyama, Eunkyung An, Shankara Anand, Meenakshi Anurag, Özgün Babur, Jasmin Bavarva, Chet Birger, Michael J. Birrer, Song Cao, Steven A. Carr, Daniel W. Chan, Arul M. Chinnaiyan, Hanbyul Cho, Karl Clauser, Antonio Colaprico, Daniel Cui Zhou, Felipe da Veiga Leprevost, Corbin Day, Saravana M. Dhanasekaran, Li Ding, Marcin J. Domagalski, Yongchao Dou, Brian J. Druker, Nathan Edwards, Matthew J. Ellis, Steven M. Foltz, Alicia Francis, Yifat Geffen, Gad Getz, David I. Heiman, Runyu Hong, Yingwei Hu, Chen Huang, Eric J. Jaehnig, Scott D. Jewell, Jiayi Ji, Wen Jiang, Lizabeth Katsnelson, Karen A. Ketchum, Iga Kolodziejczak, Karsten Krug, Chandan Kumar-Sinha, Jonathan T. Lei, Wen-Wei Liang, Yuxing Liao, Caleb M. Lindgren, Tao Liu, Wenke Liu, Jason McDermott, Wilson McKerrow, Mehdi Mesri, Michael Brodie Mumphrey, Chelsea J. Newton, Robert Oldroyd, Samuel H. Payne, Pietro Pugliese, Karin D. Rodland, Fernanda Martins Rodrigues, Kelly V. Ruggles, Sara R. Savage, Eric E. Schadt, Michael Schnaubelt, Tobias Schraink, Stephan Schürer, Zhiao Shi, Richard D. Smith, Feng Song, Yizhe Song, Vasileios Stathias, Erik P. Storrs, Jimin Tan, Nadezhda V. Terekhanova, Ratna R. Thangudu, Mathangi Thiagarajan, Liang-Bo Wang, Bo Wen, Yige Wu, Matthew A. Wyczalkowski, Lijun Yao, Qing Kay Li, Hui Zhang, Qing Zhang, Xu Zhang, Zhen Zhang. Pan-cancer proteogenomics characterization of tumor immunity . Cell , 2024; DOI: 10.1016/j.cell.2024.01.027

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Cancer keeps coming for the young. Why?

Harvard’s Kimmie Ng among gastrointestinal specialists hunting culprit behind global disease wave

Alvin Powell

Harvard Staff Writer

A report released last month by the American Cancer Society reflects significant progress in recent decades in early detection and treatment of the disease. That’s the good news. The report also highlights a disturbing new development: Higher rates of colorectal cancer among younger people. Kimmie Ng, an associate professor of medicine at Harvard Medical School and the founding director of Dana-Farber’s Young-Onset Colorectal Cancer Center , has seen this trend close-up. There’s no clear cause behind the surge, she says, but researchers are keenly interested in the “birth-cohort effect” and the potential role of environmental factors. The interview has been edited for clarity and length.

Looking at the landscape broadly, how are we doing with cancer in the U.S.?

Overall, there is good news. The number of cancer deaths has decreased significantly since the previous report. That suggests that we’ve had substantial treatment advances and, for the cancers that have screening programs, increased compliance. That has led to detection of earlier-stage cancers that are more curable. The combination of those factors has led to an overall decrease in cancer deaths, which is very encouraging.

But what concerns us is what we’re seeing in the clinic every day: More young people, otherwise healthy with no genetic syndrome, being diagnosed with very advanced stages of gastrointestinal cancers. For men under 50, colorectal cancer is now the leading cause of cancer-related death, surpassing central nervous system tumors as well as lung cancers. In women under 50, it is now the second leading cause of cancer death. These are concerning numbers and we are all working hard to understand why this is happening.

What’s your sense of possible culprits?

We see this generational change — a “birth cohort effect” — in the rise of young-onset cancers. That leads us to suspect that a recent change in an environmental exposure or a combination of exposures is contributing to the rise. The main hypothesis is that some not-as-yet-identified environmental exposure is affecting individuals, starting in early life. The exposure perhaps occurs in utero, in infancy, or during childhood. That then predisposes us to cancers at an earlier age. A lot of work has been focused on what the environmental exposures may be and what they might be doing biologically to lead to cancer development at a younger age.

“The main hypothesis is that some not-as-yet-identified environmental exposure is affecting individuals, starting in early life.” Kimmie Ng

Do you have a favored explanation — an area where you are focusing your research?

We focus on known risk factors for colorectal cancer, which is most strongly linked to diet and lifestyle factors, regardless of age. It does seem to be digestive system cancers, as a group, that are rising in young people, so there are thoughts that there’s a shared underlying etiology related to obesity — a lot of these cancers are linked to obesity.

But I have to say, most of our patients are not obese. Many are marathon runners. Many follow very healthy diets, eat organically. So we don’t know if it’s just diet and lifestyle factors or other things in our environment — pollutants, preservatives in our food. A recent paper on microplastics generated a lot of interest.

When we talk about in utero exposures, is that a situation where environmental hazards play a role?

Potentially. Certainly, maternal influences are passed to the fetus when it’s in utero, but after birth, maternal factors may still influence health risks later in life. We did a study on whether breastfeeding in infancy has any relationship to development of colorectal cancer. Very surprisingly, we found that being breastfed in infancy led to increased risks of developing colorectal cancer. We were surprised and we certainly don’t want to discourage breastfeeding. It has many other health benefits that probably outweigh the small increased risk of colorectal cancer. But it’s intriguing that as early as infancy, environmental exposures probably matter.

We’ve been talking mainly about the United States. How do we compare internationally?

This is a global phenomenon. In higher socioeconomic countries, where there are screening programs for colorectal cancer, rates are declining nicely in those over 50. For those under 50, the curve is going the opposite way, mirroring what we are seeing in the U.S. We are now seeing rises in young-onset gastrointestinal cancers in all parts of the world. Whatever is happening, we need to study this on a global level.

Screening recommendations for colorectal cancer changed recently from age 50 to 45. Do we need to go even lower?

Lowering the screening age would significantly aid in cancer prevention and decrease cancer mortality in those eligible for screening. That being said, the steepest rises that we’re seeing in this disease are in the very youngest people, those in their 20s and 30s, and they’re not eligible for screening even with the new guidelines. It’s unlikely that the U.S. Preventive Services Task Force will lower the screening age any further, so the approach that we all believe needs to be taken, urgently, is to better understand risk factors and underlying causes so that we can identify those 20-year-olds and 30-year-olds at high risk and target those folks for earlier screening.

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Science sleuths are using technology to find fakery and plagiarism in published research

FILE - A sign hangs from the Dana-Farber Cancer Institute, Aug. 18, 2022, in Boston. Dana-Farber Cancer Institute announced it’s requesting six retractions and 31 corrections of scientific papers after a British blogger flagged problems in early January 2024. (AP Photo/Charles Krupa, File)

FILE - A sign hangs from the Dana-Farber Cancer Institute, Aug. 18, 2022, in Boston. Dana-Farber Cancer Institute announced it’s requesting six retractions and 31 corrections of scientific papers after a British blogger flagged problems in early January 2024. (AP Photo/Charles Krupa, File)

This photo provided by Sholto David shows David at his home in Pontypridd, Wales, Friday, Jan. 26, 2024. David is a scientist-sleuth who detects image manipulation in published scientific papers. Dana-Farber Cancer Institute announced it is requesting six retractions and 31 corrections of scientific papers after he flagged problems in a recent blog post. (Sholto David via AP)

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Allegations of research fakery at a leading cancer center have turned a spotlight on scientific integrity and the amateur sleuths uncovering image manipulation in published research.

Dana-Farber Cancer Institute, a Harvard Medical School affiliate, announced Jan. 22 it’s requesting retractions and corrections of scientific papers after a British blogger flagged problems in early January.

The blogger, 32-year-old Sholto David, of Pontypridd, Wales, is a scientist-sleuth who detects cut-and-paste image manipulation in published scientific papers.

He’s not the only hobbyist poking through pixels. Other champions of scientific integrity are keeping researchers and science journals on their toes. They use special software, oversize computer monitors and their eagle eyes to find flipped, duplicated and stretched images, along with potential plagiarism.

Defense Secretary Lloyd Austin speaks during a Pentagon press briefing at the Pentagon on Thursday, Feb. 1, 2024 in Washington. (AP Photo/Kevin Wolf)

A look at the situation at Dana-Farber and the sleuths hunting sloppy errors and outright fabrications:

WHAT HAPPENED AT DANA-FARBER?

In a Jan. 2 blog post , Sholto David presented suspicious images from more than 30 published papers by four Dana-Farber scientists, including CEO Laurie Glimcher and COO William Hahn.

Many images appeared to have duplicated segments that would make the scientists’ results look stronger. The papers under scrutiny involve lab research on the workings of cells. One involved samples from bone marrow from human volunteers.

The blog post included problems spotted by David and others previously exposed by sleuths on PubPeer , a site that allows anonymous comments on scientific papers.

Student journalists at The Harvard Crimson covered the story on Jan. 12, followed by reports in other news media. Sharpening the attention was the recent plagiarism investigation involving former Harvard president Claudine Gay, who resigned early this year .

HOW DID DANA-FARBER RESPOND?

Dana-Farber said it already had been looking into some of the problems before the blog post. By Jan. 22, the institution said it was in the process of requesting six retractions of published research and that another 31 papers warranted corrections.

Retractions are serious. When a journal retracts an article that usually means the research is so severely flawed that the findings are no longer reliable.

Dr. Barrett Rollins, research integrity officer at Dana-Farber, said in a statement: “Following the usual practice at Dana-Farber to review any potential data error and make corrections when warranted, the institution and its scientists already have taken prompt and decisive action in 97 percent of the cases that had been flagged by blogger Sholto David.”

WHO ARE THE SLEUTHS?

California microbiologist Elisabeth Bik, 57, has been sleuthing for a decade. Based on her work, scientific journals have retracted 1,133 articles, corrected 1,017 others and printed 153 expressions of concern, according to a spreadsheet where she tracks what happens after she reports problems.

She has found doctored images of bacteria, cell cultures and western blots, a lab technique for detecting proteins.

“Science should be about finding the truth,” Bik told The Associated Press. She published an analysis in the American Society for Microbiology in 2016: Of more than 20,000 peer-reviewed papers, nearly 4% had image problems, about half where the manipulation seemed intentional.

Bik’s work brings donations from Patreon subscribers of about $2,300 per month and occasional honoraria from speaking engagements. David told AP his Patreon income recently picked up to $216 per month.

Technology has made it easier to root out image manipulation and plagiarism, said Ivan Oransky, who teaches medical journalism at New York University and co-founded the Retraction Watch blog. The sleuths download scientific papers and use software tools to help find problems.

Others doing the investigative work remain anonymous and post their findings under pseudonyms. Together, they have “changed the equation” in scientific publication, Oransky said.

“They want science to be and do better,” Oransky said. “And they are frustrated by how uninterested most people in academia — and certainly in publishing — are in correcting the record.” They’re also concerned about the erosion of public trust in science.

WHAT MOTIVATES MISCONDUCT?

Bik said some mistakes could be sloppy errors where images were mislabeled or “somebody just grabbed the wrong photo.”

But some images are obviously altered with sections duplicated or rotated or flipped. Scientists building their careers or seeking tenure face pressure to get published. Some may intentionally falsify data, knowing that the process of peer review — when a journal sends a manuscript to experts for comments — is unlikely to catch fakery.

“At the end of the day, the motivation is to get published,” Oransky said. “When the images don’t match the story you’re trying to tell, you beautify them.”

WHAT HAPPENS NEXT?

Scientific journals investigate errors brought to their attention but usually keep their processes confidential until they take action with a retraction or correction.

Some journals told the AP they are aware of the concerns raised by David’s blog post and were looking into the matter.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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Nutrition and cancer: A review of the evidence for an anti-cancer diet

Michael s donaldson.

1 Director of Research, Hallelujah Acres Foundation, 13553 Vantage Hwy, Ellensburg, WA 98926, USA

It has been estimated that 30–40 percent of all cancers can be prevented by lifestyle and dietary measures alone. Obesity, nutrient sparse foods such as concentrated sugars and refined flour products that contribute to impaired glucose metabolism (which leads to diabetes), low fiber intake, consumption of red meat, and imbalance of omega 3 and omega 6 fats all contribute to excess cancer risk. Intake of flax seed, especially its lignan fraction, and abundant portions of fruits and vegetables will lower cancer risk. Allium and cruciferous vegetables are especially beneficial, with broccoli sprouts being the densest source of sulforophane. Protective elements in a cancer prevention diet include selenium, folic acid, vitamin B-12, vitamin D, chlorophyll, and antioxidants such as the carotenoids (α-carotene, β-carotene, lycopene, lutein, cryptoxanthin). Ascorbic acid has limited benefits orally, but could be very beneficial intravenously. Supplementary use of oral digestive enzymes and probiotics also has merit as anticancer dietary measures. When a diet is compiled according to the guidelines here it is likely that there would be at least a 60–70 percent decrease in breast, colorectal, and prostate cancers, and even a 40–50 percent decrease in lung cancer, along with similar reductions in cancers at other sites. Such a diet would be conducive to preventing cancer and would favor recovery from cancer as well.

The field of investigation of the role of nutrition in the cancer process is very broad. It is becoming clearer as research continues that nutrition plays a major role in cancer. It has been estimated by the American Institute for Cancer Research and the World Cancer Research Fund that 30–40 percent of all cancers can be prevented by appropriate diets, physical activity, and maintenance of appropriate body weight [ 1 ]. It is likely to be higher than this for some individual cancers.

Most of the research on nutrition and cancer has been reductionist; that is, a particular food or a nutrient has been studied in relation to its impact on tumor formation/regression or some other end point of cancer at a particular site in the body. These studies are very helpful in seeing the details of the mechanisms of disease. However, they do not help give an overall picture of how to prevent cancer on a dietary level. Even less, they tell little of how to eat when a person already has a cancer and would like to eat a diet that is favorable to their recovery.

This review will focus on those dietary factors which has been shown to be contribute to increased risk of cancer and then on those additional protective dietary factors which reduce cancer risk. Finally, some whole-diet studies will be mentioned which give a more complete picture of how these individual factors work together to reduce cancer risk.

Over Consumption of Energy (Calories)

Eating too much food is one of the main risk factors for cancer. This can be shown two ways: (1) by the additional risks of malignancies caused by obesity, and (2) by the protective effect of eating less food.

Obesity has reached epidemic proportions in the United States. Sixty-four percent of the adult population is overweight or obese [ 2 ]. About 1 in 50 are now severely obese (BMI > 40 kg/m2) [ 3 ]. Mokdad et al [ 4 ] found that poor diet and physical inactivity was the second leading cause of death (400,000 per year in the USA), and would likely overtake tobacco as the leading cause of death.

It was estimated in a recent study, from a prospective cancer prevention cohort, that overweight and obesity accounted for 14 percent of all cancer deaths in men and 20 percent of those in women [ 5 ]. Significant positive associations were found between obesity and higher death rates for the following cancers: esophagus, colon and rectum, liver, gallbladder, pancreas, kidney, stomach (in men), prostate, breast, uterus, cervix, and ovary [ 5 ]. The authors estimated that over 90,000 cancer deaths per year could be avoided if the adult population all maintained a normal weight (BMI < 25.0) [ 5 ]. Clearly, obesity is a major risk factor for cancer.

On the other side, careful menu planning brings about an approach entitled CRON-Calorie Restriction with Optimal Nutrition. The basic idea is to eat a reduced amount of food (about 70–80 percent of the amount required to maintain "normal" body weight) while still consuming all of the necessary amounts of vitamins, minerals, and other necessary nutrients. The only restriction is the total amount of energy (calories) that is consumed. While being difficult to practice, this approach has a lot of scientific merit for being able to extend average life spans of many species of animals including rats, mice, fish, and possibly primates (currently being tested). Along with this life span extension is a reduction in chronic diseases that are common to mankind, reviewed in Hursting et al [ 6 ]. A recent meta-analysis of 14 experimental studies found that energy restriction resulted in a 55% reduction in spontaneous tumors in laboratory mice [ 7 ]. Calorie restriction inhibited induced mammary tumors in mice [ 8 ] and suppressed implanted tumor growth and prolonged survival in energy restricted mice [ 9 ]. Among Swedish women who had been hospitalized for anorexia nervosa (definitely lower caloric intake, but not adequate nutrition) prior to age 40, there was a 23% lower incidence of breast cancer for nulliparous women and a 76% lower incidence for parous women [ 10 ]. So, too many calories is definitely counter-productive, and slightly less than normal is very advantageous.

Glucose Metabolism

Refined sugar is a high energy, low nutrient food – junk food. "Unrefined" sugar (honey, evaporated cane juice, etc) is also very concentrated and is likely to contribute to the same problems as refined sugar. Refined wheat flour products are lacking the wheat germ and bran, so they have 78 percent less fiber, an average of 74 percent less of the B vitamins and vitamin E, and 69 percent less of the minerals (USDA Food database, data not shown). Concentrated sugars and refined flour products make up a large portion of the carbohydrate intake in the average American diet. One way to measure the impact of these foods on the body is through the glycemic index.

The glycemic index is an indication of the blood sugar response of the body to a standardized amount of carbohydrate in a food. The glycemic load takes into account the amount of food eaten. An international table of the glycemic index and glycemic load of a wide variety of foods has been published [ 11 ].

Case-control studies and prospective population studies have tested the hypothesis that there is an association between a diet with a high glycemic load and cancer. The case control studies have found consistent increased risk of a high glycemic load with gastric [ 12 ], upper aero digestive tract [ 13 ], endometrial [ 14 ], ovarian [ 15 ], colon or colorectal cancers [ 16 , 17 ]. The prospective studies' results have been mixed. Some studies showed increased risk of cancer in the whole cohort with high glycemic load [ 18 - 20 ]; some studies found only increased risk among subgroups such as sedentary, overweight subjects [ 21 - 24 ]; other studies concluded that there was no increased risk for any of their cohort [ 25 - 28 ]. Even though there were no associations between glycemic load and colorectal, breast, or pancreatic cancer in the Nurses' Health Study there was still a strong link between diabetes and colorectal cancer [ 29 ].

Perhaps the dietary glycemic load is not consistently related to glucose disposal and insulin metabolism due to individual's different responses to the same glycemic load. Glycated hemoglobin (HbA 1c ) is a time-integrated measurement of glucose control, and indirectly, of insulin levels. Increased risk in colorectal cancer was seen in the EPIC-Norfolk study with increasing HbA 1c ; subjects with known diabetes had a three-fold increased risk of colorectal cancer [ 30 ]. In a study of a cohort in Washington county, Maryland, increased risk of colorectal cancer was seen in subjects with elevated HbA 1c , BMI > 30 kg/m 2 , or who used medications to control diabetes [ 31 ]. However, glycated hemoglobin was not found to be associated with increased risk of colorectal cancer in a small nested case-control study within the Nurses' Health Study [ 32 ]. Elevated fasting glucose, fasting insulin, 2 hour levels of glucose and insulin after an oral glucose challenge, and larger waist circumference were associated with a higher risk of colorectal cancer [ 33 ]. In multiple studies diabetes has been linked with increased risk of colorectal cancer [ 34 - 37 ], endometrial cancer [ 38 ], and pancreatic cancer [ 35 , 39 ]. It is clear that severe dysregulation of glucose metabolism is a risk factor for cancer. Foods which contribute to hyperinsulinemia, such as refined sugar, foods containing refined sugar, and refined flour products should be avoided and eliminated from a cancer protective diet.

Unrefined plant foods typically have an abundance of fiber. Dairy products, eggs, and meat all have this in common – they contain no fiber. Refined grain products also have most of the dietary fiber removed from them. So, a diet high in animal products and refined grains (a typical diet in the USA) is low in fiber. In prospective health studies low fiber was not found to be a risk for breast cancer [ 25 ]. It is possible that fiber measurements are just a surrogate measure for unrefined plant food intake. Slattery et al [ 40 ] found an inverse correlation between vegetable, fruit and whole grain intake plant food intake and rectal cancer, while refined grains were associated with increased risk of rectal cancer. A threshold of about 5 daily servings of vegetables was needed to reduce cancer risk and the effect was stronger among older subjects [ 40 ]. Many other nutrients are co-variants with fiber, including folic acid, which is covered in detail below.

Red meat has been implicated in colon and rectal cancer. A Medline search in February 2003 uncovered 26 reports of human studies investigating the link between diet and colon or colorectal cancer. Of the 26 reports, 21 of them reported a significant positive relationship between red meat and colon or colorectal cancer [ 17 , 41 - 64 ]. A recent meta-analysis also found red meat, and processed meat, to be significantly associated with colorectal cancer [ 65 ]. Meat, and the heterocyclic amines formed in cooking, have been correlated to breast cancer in a case-control study in Uruguay as well [ 66 ].

Omega 3:6 Ratio Imbalance

Omega 3 fats (alpha-linolenic acid, EPA, DHA) have been shown in animal studies to be protect from cancer, while omega 6 fats (linoleic acid, arachidonic acid) have been found to be cancer promoting fats. Now there have been several studies that have tested this hypothesis in relation to breast cancer, summarized in Table ​ Table1. 1 . Except for the study by London et al [ 67 ], all of these studies found an association between a higher ratio of N-3 to N-6 fats and reduced risk of breast cancer. Long chain N-3 and N-6 fats have a different effect on the breast tumor suppressor genes BRCA1 and BRCA2. Treatment of breast cell cultures with N-3 fats (EPA or DHA) results in increased expression of these genes while arachadonic acid had no effect [ 68 ]. Flax seed oil and DHA (from an algae source) both can be used to increase the intake of N-3 fat, with DHA being a more efficient, sure source.

Breast Cancer and Omega 3:6 Ratio.

Flax seed provides all of the nutrients from this small brown or golden hard-coated seed. It is an excellent source of dietary fiber, omega 3 fat (as alpha-linolenic acid), and lignans. The lignans in flax seed are metabolized in the digestive tract to enterodiol and enterolactone, which have estrogenic activity. In fact, flax seed is a more potent source of phytoestrogens than soy products, as flax seed intake caused a bigger change in the excretion of 2-hydroxyestrone compared to soy protein [ 69 ].

Ground flax seeds have been studied for its effect on cancer, including several excellent studies by Lilian Thompson's research group at the University of Toronto. In one study the flax seed, its lignan fraction, or the oil were added to the diet of mice who had previously been administered a chemical carcinogen to induce cancer. All three treatments reduced the established tumor load; the lignan fraction containing secoisolariciresinol diglycoside (SDG) and the flax seed also reduced metastasis [ 70 ]. In another study the flax lignan SDG was fed to mice starting 1 week after treatment with the carcinogen dimethylbenzanthracene. The number of tumors per rat was reduced by 46% compared to the control in this study [ 71 ]. Flax or its lignan (SDG) were tested to see if they would prevent melanoma metastasis. The flax or lignan fraction were fed to mice two weeks before and after injection of melanoma cells. The flax treatment (at 2.5, 5, or 10% of diet intake) resulted in a 32, 54, and 63 percent reduction in the number of tumors, compared to the control [ 72 ]. The SDG, fed at amounts equivalent to the amount in 2.5, 5, or 10% flax seed, also reduced the tumor number, from a median number of 62 in the control group to 38, 36, and 29 tumors per mouse in the SDG groups, respectively [ 73 ].

More recently Thompson's research group studied mice that were injected with human breast cancer cells. After the injection the mice were fed a basal diet (lab mouse chow) for 8 weeks while the tumors grew. Then one group continued the basal diet and another was fed a 10% flax seed diet. The flax seed reduced the tumor growth rate and reduced metastasis by 45% [ 74 ].

Flax seed has been shown to enhance mammary gland morphogenesis or differentiation in mice. Nursing dams were fed the 10% flax seed diet (or an equivalent amount of SDG). After weaning the offspring mice were fed a regular mouse chow diet. Researchers then examined the female offspring and found an increased number of terminal end buds and terminal ducts in their mammary glands with more epithelial cell proliferation, all demonstrating that mammary gland differentiation was enhanced [ 75 ]. When these female offspring were challenged with a carcinogen to induce mammary gland tumors there were significantly lower incidence of tumors (31% and 42% lower in the flax seed and SDG groups, respectively), significantly lower tumor load (51% and 62% lower in the flax seed and SDG groups, respectively), significantly lower mean tumor size (44% and 68% lower in the flax seed and SDG groups, respectively), and significantly lower tumor number (47% and 45% lower in the flax seed and SDG groups, respectively) [ 76 ]. So, flax seed and its lignan were able to reduce tumor growth (both in number and size of tumors), prevent metastasis, and even cause increased differentiation of mouse mammary tissue in suckling mice, making the offspring less susceptible to carcinogenesis even when not consuming any flax products.

Other researchers have tested flax seed and prostate cancer. In an animal model using mice, Lin et al [ 77 ] found that a diet supplemented with 5% flax inhibited the growth and development of prostate cancer in their experimental mouse model. A pilot study of 25 men who were scheduled for prostatectomy surgery were instructed to eat a low-fat diet (20% or less of energy intake) and to supplement with 30 g of ground flaxseed per day. During the follow-up of an average of 34 days there were significant changes in serum cholesterol, total testosterone, and the free androgen index [ 78 ]. The mean proliferation index of the experimental group was significantly lower and apoptotic indexes higher compared to historical matched controls. Ground flax seed may be a very beneficial food for men battling prostate cancer. However, a meta-analysis of nine cohort and case-control studies revealed an association between flax seed oil intake or high blood levels of alpha-linolenic acid and prostate cancer risk [ 79 ]. It is quite likely that the lignans in flax seed are a major component of flax's anti-cancer effects so that flax oil without the lignans is not very beneficial. Some brands of flax seed oil retain some of the seed particulate because of the beneficial properties of the lignans.

Fruits and Vegetables

One of the most important messages of modern nutrition research is that a diet rich in fruits and vegetables protects against cancer. (The greatest message is that this same diet protects against almost all other diseases, too, including cardiovascular disease and diabetes.) There are many mechanisms by which fruits and vegetables are protective, and an enormous body of research supports the recommendation for people to eat more fruits and vegetables.

Block et al [ 80 ] reviewed about 200 studies of cancer and fruit and vegetable intake. A statistically significant protective effect of fruits and vegetables was found in 128 of 156 studies that gave relative risks. For most cancers, people in the lower quartile (1/4 of the population) who ate the least amount of fruits and vegetables had about twice the risk of cancer compared to those who in the upper quartile who ate the most fruits and vegetables. Even in lung cancer, after accounting for smoking, increasing fruits and vegetables reduces lung cancer; an additional 20 to 33 percent reduction in lung cancers is estimated [ 1 ].

Steinmetz and Potter reviewed the relationship between fruits, vegetables, and cancer in 206 human epidemiologic studies and 22 animal studies [ 81 ]. They found "the evidence for a protective effect of greater vegetable and fruit consumption is consistent for cancers of the stomach, esophagus, lung, oral cavity and pharynx, endometrium, pancreas, and colon." Vegetables, and particularly raw vegetables, were found to be protective; 85% of the studies that queried raw vegetable consumption found a protective effect. Allium vegetables, carrots, green vegetables, cruciferous vegetables, and tomatoes also had a fairly consistent protective effect [ 81 ]. Allium vegetables (garlic, onion, leeks, and scallions) are particularly potent and have separately been found to be protective for stomach and colorectal cancers [ 82 , 83 ] and prostate cancer [ 84 ].

There are many substances that are protective in fruits and vegetables, so that the entire effect is not very likely to be due to any single nutrient or phytochemical. Steinmetz and Potter list possible protective elements: dithiolthiones, isothiocyanates, indole-32-carbinol, allium compounds, isoflavones, protease inhibitors, saponins, phytosterols, inositol hexaphosphate, vitamin C, D-limonene, lutein, folic acid, beta carotene (and other carotenoids), lycopene, selenium, vitamin E, flavonoids, and dietary fiber [ 81 ].

A joint report by the World Cancer Research Fund and the American Institute for Cancer Research found convincing evidence that a high fruit and vegetable diet would reduce cancers of the mouth and pharynx, esophagus, lung, stomach, and colon and rectum; evidence of probable risk reduction was found for cancers of the larynx, pancreas, breast, and bladder [ 1 ].

Many of the recent reports from prospective population-based studies of diet and cancer have not found the same protective effects of fruits and vegetables that were reported earlier in the epidemiological and case-control studies [reviewed in [ 85 ]]. One explanation is that people's memory of what they ate in a case-cohort study may have been tainted by their disease state. Another problem might be that the food frequency questionnaires (FFQ) used to measure food intake might not be accurate enough to detect differences. Such a problem was noted in the EPIC study at the Norfolk, UK site. Using a food diary the researchers found a significant correlation between saturated fat intake and breast cancer, but using a FFQ there was no significant correlation [ 86 ]. So, inaccurate measurement of fruit and vegetable intake might be part of the explanation as well.

It must be noted that upper intakes of fruits and vegetables in these studies are usually within the range of what people on an American omnivorous diet normally eat. In the Nurses Health Study the upper quintiles of fruit and vegetable intake were 4.5 and 6.2 servings/day, respectively [ 87 ]. Similarly, the upper quintiles of fruit and vegetable intake in the Health Professionals Follow-up Study were 4.3 and 5.4 serving/day for fruits and vegetables, respectively [ 87 ]. Intakes of fruits and vegetables on the Hallelujah Diet are much higher, with median reported intakes of six servings of fruits (646 g/day) and eleven servings of vegetables per day (971 g/day) [ 88 ] in addition to a green powder from the juice of barley leaves and alfalfa that is equivalent to approximately another 100 g/day of fresh dark greens. So, it is very possible that the range of intakes in the prospective population based studies do not have a wide enough intake on the upper end to detect the true possible impact of a very high intake of fruits and vegetables on cancer risk.

Cruciferous Vegetables

Cruciferous vegetables (broccoli, cauliflower, cabbage, Brussels sprouts) contain sulforophane, which has anti-cancer properties. A case-control study in China found that intake of cruciferous vegetables, measured by urinary secretion of isothiocyanates, was inversely related to the risk of breast cancer; the quartile with the highest intake only had 50% of the risk of the lowest intake group [ 89 ]. In the Nurses' Health Study a high intake of cruciferous vegetables (5 or more servings/week vs less than two servings/week) was associated with a 33% lower risk of non-Hodgkin's lymphoma [ 90 ]. In the Health Professionals Follow-up Study bladder cancer was only weakly associated with low intake of fruits and vegetables, but high intake (5 or more servings/week vs 1 or less servings/wk) of cruciferous vegetables was associated with a statistically significant 51% decrease in bladder cancer [ 91 ]. Also, prostate cancer risk was found to be reduced by cruciferous vegetable consumption in a population-based case-control study carried out in western Washington state. Three or more servings per week, compared to less than one serving of cruciferous vegetables per week resulted in a statistically significant 41% decrease in prostate cancer risk [ 92 ]. Similar protective effects of cruciferous vegetables were seen in a multi-ethnic case-control study [ 93 ]. A prospective study in Shanghai, China found that men with detectable amounts of isothiocyanates in their urine (metabolic products that come from cruciferous vegetables) had a 35% decreased risk of lung cancer. Among men that had one or two genetic polymorphisms that caused them to eliminate these isothiocyanates slower there was a 64% or 72% decreased risk of lung cancer, respectively [ 94 ].

Broccoli sprouts have a very high concentration of sulforophane since this compound originates in the seed and is not made in the plant as it grows [ 95 , 96 ]. One sprout contains all of the sulforophane that is present in a full-grown broccoli plant. So, if sulforophane is especially cancer-protective, it would seem reasonable to include some broccoli sprouts in an anti-cancer diet.

Selenium is a mineral with anti-cancer properties. Many studies in the last several years have shown that selenium is a potent protective nutrient for some forms of cancer. The Arizona Cancer Center posted a selenium fact sheet listing the major functions of selenium in the body [ 97 ]. These functions are as follows:

1. Selenium is present in the active site of many enzymes, including thioredoxin reductase, which catalyze oxidation-reduction reactions. These reactions may encourage cancerous cells to under apoptosis.

2. Selenium is a component of the antioxidant enzyme glutathione peroxidase.

3. Selenium improved the immune systems' ability to respond to infections.

4. Selenium causes the formation of natural killer cells.

5. P450 enzymes in the liver may be induced by selenium, leading to detoxification of some carcinogenic molecules.

6. Selenium inhibits prostaglandins that cause inflammation.

7. Selenium enhances male fertility by increased sperm motility.

8. Selenium can decrease the rate of tumor growth.

A serendipitous randomized, double-blind, controlled trial of a 200 μg/day selenium supplement in the southeastern region of the USA (where soil selenium levels are low) found that the primary endpoints of skin cancer were not improved by the selenium supplement, but that other cancer incidence rates were decreased by selenium [ 98 , 99 ]. There was a significant reduction in total cancer incidence (105 vs 137 cases, P = 0.03), prostate cancer (22 vs 42 cases, P = 0.005), a marginally significant reduction in colorectal cancer incidence (9 vs 19 cases, P = 0.057), and a reduction in cancer mortality, all cancer sites (40 vs 66 deaths, P = 0.008) (selenium versus control group cases reported, respectively) [ 98 ]. The selenium supplement was most effective in ex-smokers and for those who began the study with the lowest levels of serum selenium. Several prospective studies have also examined the role of selenium in cancer prevention, particularly for prostate cancer, summarized in Table ​ Table2 2 .

Prospective Nested Case Control Studies of Selenium and Prostate Cancer.

Overall, it appears that poor selenium levels, especially for men, are a cancer risk. If a person has low selenium levels and other antioxidant defenses are also low the cancer risk is increased even further. Women do not appear to be as sensitive to selenium, as breast cancer has not been found to be influenced by selenium status in several studies [ 100 - 104 ], although both men and women were found to be protected by higher levels of selenium from colon cancer [ 100 ] and lung cancer [ 105 , 106 ]. Good vegetarian sources of selenium are whole grains and legumes grown in selenium-rich soil in the western United States, brazil nuts (by far the most dense source of selenium), nutritional yeast, brewers yeast, and sunflower seeds.

Chlorophyll

All green plants also contain chlorophyll, the light-collecting molecule. Chlorophyll and its derivatives are very effective at binding polycyclic aromatic hydrocarbons (carcinogens largely from incomplete combustion of fuels), heterocyclic amines (generated when grilling foods), aflatoxin (a toxin from molds in foods which causes liver cancer), and other hydrophobic molecules. The chlorophyll-carcinogen complex is much harder for the body to absorb, so most of it is swept out with the feces. The chemoprotective effect of chlorophyll and its derivatives has been tested in laboratory cell cultures and animals [ 107 , 108 ]. There is so much compelling evidence for anti-carcinogenic effects of chlorophyll that a prospective randomized controlled trial is being conducted in Qidong, China to see if chlorophyllin can reduce the amount of liver cancer cases, which arise from aflatoxin exposure in their foods (corn, peanuts, soy sauce, and fermented soy beans). A 55% reduction in aflatoxin-DNA adducts were found in the group that took 100 mg of chlorophyllin three times a day [ 109 ]. It was supposed that the chlorophyllin bound up aflatoxins, but there were chlorophyllin derivatives also detected in the sera (which had a green tint to it) of the volunteers who took the supplement, indicating a possible role in the body besides binding carcinogens in the gut [ 110 ].

Protective Vitamins

Vitamin b-12.

Vitamin B-12 has not been proven to be an anti-cancer agent, but there is some evidence indicating that it could be beneficial. The form of administered vitamin B-12 may be important.

Some experimental cancer studies have been carried out with various forms of vitamin B-12. Methylcobalamin inhibited tumor growth of SC-3 injected into mice [ 111 ], and caused SC-3 mouse mammary tumor cells to undergo apoptosis, even when stimulated to grow by the presence of growth-inducing androgen [ 112 ]. Methylcobalamin, but not cyanocobalamin, increased the survival time of mice bearing implanted leukemia tumor cells [ 113 ]. 5'-deoxyadenosylcobalamin and methylcobalamin, but not cyanocobalamin, were shown to be effective cytotoxic agents [ 114 ]. Methylcobalamin also was able to increase survival time and reduce tumor growth in laboratory mice [ 115 ].

Laboratory mechanistic evidence for the effects of vitamin B12 were seen in a laboratory study with vitamin B-12 deficient rats. Choi et al [ 116 ] found that the colonic DNA of the B-12 deficient rats had a 35% decrease in genomic methylation and a 105% increase in uracil incorporation, both changes that could increase risk of carcinogenesis. In two prospective studies (one in Washington Country, Maryland and the Nurses' Health Study) a relation between lower vitamin B12 status (but not deficiency) and statistically significant higher risk of breast cancer was found [ 117 , 118 ]. So, there is evidence from laboratory studies, prospective cohort studies, and mechanistic studies showing that vitamin B-12 is an important nutrient for genetic stability, DNA repair, carcinogenesis, and cancer therapy.

Folic acid is the dark green leafy vegetable vitamin. It has an integral role in DNA methylation and DNA synthesis. Folic acid works in conjunction with vitamin B-6 and vitamin B-12 in the single carbon methyl cycle. If insufficient folic acid is not available uracil is substituted for thymidine in DNA, which leads to DNA strand breakage. About 10% of the US population (and higher percentages among the poor) has low enough intakes of folic acid to make this a common problem [ 119 ]. As shown in Tables ​ Tables3 3 and ​ and4, 4 , many studies have found a significant reduction in colon, rectal, and breast cancer with higher intakes of folic acid and their related nutrients (vitamin B-6 and B-12). Alcohol is an antagonist of folate, so that drinking alcoholic beverages greatly magnifies the cancer risk of a low-folate diet. Genetic polymorphisms (common single DNA base mutations resulting in a different amino acid encoded into a protein) in the methylenetetrahydrofolate reductase and the methionine synthase genes which increase the relative amount of folate available for DNA synthesis and repair also reduces the risk of colon cancer [ 120 - 123 ]. Cravo et al [ 124 ] used 5 mg of folic acid a day (a supraphysiological dose) in a prospective, controlled, cross-over study of 20 patients with colonic adenoma polyps. They found that the folic acid could reverse DNA hypomethylation in 7 of 12 patients who had only one polyp.

Folate and Colon / Rectal Cancer.

SS = statistically significant

Prospective Studies of Folate and Breast Cancer.

FH = Family History

Folate may be more important for rapidly dividing tissue, like the colonic mucosa. Therefore, the cancer risk associated with low folate intake is probably higher for colon cancer than for breast cancer. Most of the breast cancer studies only found a protective effect of folate among women who consumed alcohol (see Table ​ Table4). 4 ). However, among women residents of Shanghai who consumed no alcohol, no vitamin supplements and ate unprocessed, unfortified foods there was a 29% decreased risk of breast cancer among those with the highest intake of folate [ 125 ]. So, there may be a true protective effect that is masked in the western populations by so many other risk factors. Two studies showed that the risk of cancer due to family history can be modified by high folate intake, so a prudent anti-cancer diet would be high in dark green leafy vegetables. The mean intake of folic acid on the Hallelujah Diet was 594 μg/day for men and 487 μg/day for women [ 88 ].

Vitamin D is produced primarily from the exposure of the skin to sunshine. Even casual exposure of the face, hands, and arms in the summer generates a large amount of vitamin D. In fact, simulated sunshine, equivalent to standing on a sunny beach until a slight pinkness of the skin was detected, was equivalent to a 20,000 IU oral dose of vitamin D 2 [ 126 ]. (Note that the RDA is 400 IU for most adults.) It has been estimated that 1,000 IU per day is the minimal amount needed to maintain adequate levels of vitamin D in the absence of sunshine [ 126 ], and that up to 4,000 IU per day can be safely used with additional benefit [ 127 ].

The concentration of the active hormonal form of vitamin D is tightly regulated in the blood by the kidneys. This active hormonal form of vitamin D has the potent anti-cancer properties. It has been discovered that various types of normal and cancerous tissues, including prostate cells [ 128 ], colon tissue [ 129 ], breast, ovarian and cervical tissue [ 130 ], pancreatic tissue [ 131 ] and a lung cancer cell line [ 132 ] all have the ability to convert the major circulating form of vitamin D, 25(OH)D, into the active hormonal form, 1,25(OH) 2 D. So, there is a local mechanism in many tissues of the body for converting the form of vitamin D in the body that is elevated by sunshine exposure into a hormone that has anticancer activity.

Indeed, 25(OH)D has been shown to inhibit growth of colonic epithelial cells [ 133 ], primary prostatic epithelial cells [ 134 ], and pancreatic cells [ 131 ]. So, the laboratory work is confirming what had been seen some time ago in ecological studies of populations and sunshine exposure.

The mortality rates for colon, breast, and ovary cancer in the USA show a marked north-south gradient [ 135 ]. In ecological studies of populations and sunlight exposure (no individual data) sunlight has been found to have a protective effect for prostate cancer [ 136 ], ovarian cancer [ 137 ], and breast cancer [ 138 ]. Recently Grant found that sunlight was also protective for bladder, endometrial, renal cancer, multiple myeloma, and Non-Hodgkins lymphoma in Europe [ 139 ] and bladder, esophageal, kidney, lung, pancreatic, rectal, stomach, and corpus uteri cancer in the USA [ 140 ]. Several prospective studies of vitamin D and cancer have also shown a protective effect of vitamin D (see Table ​ Table5). 5 ). It could be that sunshine and vitamin D are protective factors for cancers of many organs that can convert 25(OH)D into 1,25(OH)D 2 .

Prospective Studies of Vitamin D and Cancer.

Antioxidants

α- and β-carotene and other carotenoids.

Carotenoids have been studied vigorously to see if these colorful compounds can decrease cancer risk. In ecological studies and early case-control studies it appeared that β-carotene was a cancer-protective agent. Randomized controlled trials of β-carotene found that the isolated nutrient was either neutral [ 141 ] or actually increased risk of lung cancer in smokers [ 142 , 143 ]. Beta-carotene may be a marker for intake of fruits and vegetables, but it does not have a powerful protective effect in isolated pharmacological doses.

However, there is a large body of literature that indicates that dietary carotenoids are cancer preventative (See Table ​ Table6). 6 ). Alpha-carotene has been found to be a stronger protective agent than its well-known isomer β-carotene. Studies tend to agree that overall intake of carotenoids is more protective than a high intake of a single carotenoid. So, a variety of fruits and vegetables is still a better anti-cancer strategy than just using a single vegetable high in a specific carotenoid.

Studies of Carotenoids and Lung Cancer.

SS = statistically significant difference between comparison groups.

The richest source of α-carotene is carrots and carrot juice, with pumpkins and winter squash as a second most-dense source. There is approximately one μg of α-carotene for every two μg of β-carotene in carrots. The most common sources of β-cryptoxanthin are citrus fruits and red sweet peppers.

Of the various carotenoids lycopene has been found to be very protective, particularly for prostate cancer. The major dietary source of lycopene is tomatoes, with the lycopene in cooked tomatoes being more bioavailable than that in raw tomatoes. Several prospective cohort studies have found associations between high intake of lycopene and reduced incidence of prostate cancer, though not all studies have produced consistent results [ 144 , 145 ]. Some studies suffer from a lack of good correlation between lycopene intake assessed by questionnaire and actual serum levels, and other studies measured intakes among a population that consumed very few tomato products. The studies with positive results will be reviewed here.

In the Health Professionals Follow-up Study there was a 21% decrease in prostate cancer risk, comparing the highest quintile of lycopene intake with the lowest quintile. Combined intake of tomatoes, tomato sauce, tomato juice, and pizza (which accounted for 82% of the lycopene intake) were associated with a 35% lower risk of prostate cancer. Furthermore, lycopene was even more protective for advanced stages of prostate cancer, with a 53% decrease in risk [ 146 ]. A more recent follow-up report on this same cohort of men confirmed these original findings that lycopene or frequent tomato intake is associated with about a 30–40% decrease in risk of prostate cancer, especially advanced prostate cancer [ 147 ].

In addition to the two reports above a nested case control study from the Health Professional Follow-up Study with 450 cases and controls found an inverse relation between plasma lycopene and prostate cancer risk (OR 0.48) among older subjects (>65 years of age) without a family history of prostate cancer [ 148 ]. Among younger men high plasma β-carotene was associated with a statistically significant 64% decrease in prostate cancer risk. So, the results for lycopene have been found for dietary intakes as well as plasma levels.

In a nested case-control study from the Physicians' Health Study cohort, a placebo-controlled study of aspirin and β-carotene, there was a 60% reduction in advanced prostate cancer risk (P-trend = 0.006) for those subjects in the placebo group with the highest plasma lycopene levels, compared to the lowest quintile. The β-carotene also had a protective effect, especially for those men with low lycopene levels [ 149 ].

In addition to these observational studies, two clinical trials have been conducted to supplement lycopene for a short period before radical prostatectomy. In one study 30 mg/day of lycopene were given to 15 men in the intervention group while the 11 men were in the control group were instructed to follow the National Cancer Institute's recommendations to consume at least 5 servings of fruits and vegetables daily. Results showed that the lycopene slowed the growth of prostate cancer. Prostate tissue lycopene concentration was 47% higher in the intervention group. Subjects that took the lycopene for 3 weeks had smaller tumors, less involvement of the surgical margins, and less diffuse involvement of the prostate by pre-cancerous high-grade prostatic intraepithelial neoplasia [ 150 ]. In another study before radical prostatectomy surgery 32 men were given a tomato sauce-based pasta dish every day, which supplied 30 mg of lycopene per day. After 3 weeks serum and prostate lycopene levels increaed 2-fold and 2.9-fold, respectively. PSA levels decreased 17%, as seen also by Kucuk et al [ 150 ]. Oxidative DNA damage was 21% lower in subjects' leukocytes and 28% lower in prostate tissue, compared to non-study controls. The apoptotic index was 3-fold higher in the resected prostate tissue, compared to biopsy tissue [ 151 ]. These intervention studies raise the question of what could have been done in this intervention was longer and combined synergistically with other effective intervention methods, such as flax seed, increased selenium and possibly vitamin E, in the context of a diet high in fruits and vegetable?

Vitamin C, or ascorbic acid, has been studied in relation to health and is the most common supplement taken in the USA. Low blood levels of ascorbic acid are detrimental to health (for a recent article see Fletcher et al [ 152 ]) and vitamin C is correlated with overall good health and cancer prevention [ 153 ]. Use of vitamin C for cancer therapy was popularized by Linus Pauling. At high concentrations ascorbate is preferentially toxic to cancer cells. There is some evidence that large doses of vitamin C, either in multiple divided oral doses or intravenously, have beneficial effects in cancer therapy [ 154 - 156 ]. Oral doses, even in multiple divided doses, are not as effective as intravenous administration. Vitamin C at a dose of 1.25 g administered orally produced mean peak plasma concentrations of 135 ± 21 μmol/L compared with 885 ± 201 μmol/L for intravenous administration [ 154 ].

While vitamin C is quite possibly an effective substance, the amounts required for these therapeutic effects are obviously beyond dietary intakes. However, intravenous ascorbate may be a very beneficial adjuvant therapy for cancer with no negative side effects when administered properly.

Other Antioxidants

There are many more substances that will have some benefit for cancer therapy. Most of these substances are found in foods, but their effective doses for therapy are much higher than the normal concentration in the food. For example, grape seed extract contains proanthocyanidin, which shows anticarcinogenic properties (reviewed by Cos et al \ [ 157 ]. Also, green tea contains a flavanol, epigallocatechin-3-gallate (EGCG), which can inhibit metalloproteinases, among several possible other mechanisms [ 158 ]. And there are claims for various other herbal substances and extracts that might be of benefit, which are beyond the scope of this review.

The bacteria that reside in the intestinal tract generally have a symbiotic relationship with their host. Beneficial bacteria produce natural antibiotics to keep pathogenic bugs in check (preventing diarrhea and infections) and produce some B vitamins in the small intestine where they can be utilized. Beneficial bacteria help with food digestion by providing extra enzymes, such as lactase, in the small intestine. Beneficial bacteria help strengthen the immune system right in the gut where much of the interaction between the outside world and the body goes on. Beneficial bacteria can help prevent food allergies. They can help prevent cancer at various stages of development. These good bacteria can improve mineral absorption, maximizing food utilization.

However, the balance of beneficial and potentially pathogenic bacteria in the gut is dependent on the diet. Vegetable fiber encourages the growth of beneficial bacteria. A group of Adventist vegetarians was found to have a higher amount of beneficial bacteria and lower amount of potentially pathogenic bacteria compared to non-vegetarians on a conventional American diet [ 159 ]. Differences in bacterial populations were seen between patients who recently had a colon polyp removed, Japanese-Hawaiians, North American Caucasians, native rural Japanese, and rural native Africans. Lactobacillus species and Eubacterium aerofaciens , both producers of lactic acid, were associated with the populations with the lower risk of colon cancer, while Bacteroides and Bifidobacterium species were associated with higher risk of colon cancer [ 160 ]

There is a solid theoretical basis for why probiotics should help prevent cancer, especially colon cancer, and even reverse cancer. Probiotics produce short chain fatty acids in the colon, which acidify the environment. Lower colon pH is associated with lower incidence of colon cancer. Probiotic bacteria reduce the level of procarcinogenic enzymes such as beta-glucuronidase, nitroreductase, and azoreductase [ 161 ].

L. casei was used in two trials of patients with superficial bladder cancer. In the first trial, the probiotic group had a 50% disease free time of 350 days, compared to 195 days for the control group [ 162 ]. The second trial also showed that the probiotics worked better than the placebo, except for multiple recurring tumors [ 163 ].

Except for the two studies noted above, most of the research of probiotics and cancer has been done in animals. Studies have looked at markers of tumor growth or at animals with chemically induced tumors.

Studies in rats have shown that probiotics can inhibit the formation of aberrant crypt foci, thought to be a pre-cancerous lesion in the colon. Some of the best results were obtained with a probiotic strain consumed with inulin, a type of fructooligosaccharide. Total aberrant crypt foci, chemically induced, were reduced 74% by the treatment of rats with inulin and B. longum , but only 29 and 21% by B. longum and inulin alone, respectively [ 164 ]. There was a synergistic effect in using both products together. Similar synergy was seen in rats with azoxymethane-induced colon cancer in another study. Rats fed Raftilose, a mixture of inulin and oligofructose, or Raftilose with Lactobacilli rhamnosus (LGG) and Bifidobacterium lactis (Bb12) had a significantly lower number of tumors compared to the control group [ 165 ]. A probiotic mixture, without any prebiotic, given to rats fed azoxymethane reduced colon tumors compared to the control (50% vs 90%), and also reduced the number of tumors per tumor-bearing rat [ 166 ].

In lab mice bred to be susceptible to colitis and colon cancer, a probiotic supplement, Lactobacillus salivarium ssp. Salivarius UCC118, reduced fecal coliform levels, the number of potentially pathogenic Clostridium perfringens , and reduced intestinal inflammation. In this small study two mice died of fulminant colitis and 5 mice developed adenocarcinoma in the control group of 10 mice, while there was no colitis and only 1 mouse with adenocarcinoma in the probiotic test group [ 167 ].

The research on probiotics and disease is still an emerging field. There is a high degree of variation of health benefits between different strains of bacteria. As new methods for selecting and screening probiotics become available, the field will be able to advance more rapidly.

Oral Enzymes

Many people diagnosed with cancer have digestion or intestinal tract disorders as well. Impaired digestion will greatly hinder a nutritional approach to treating cancer. If the nutrients cannot be released from the food and taken up by the body, then the excellent food provided by the Hallelujah Diet will go to waste. Digestive enzyme supplements are used to ensure proper and adequate digestion of food. Even raw foods, which contain many digestive enzymes to assist in their digestion, will be more thoroughly digested with less of the body's own resources with the use of digestive enzymes. So, the enzymes taken with meals do not have a direct effect upon a tumor, but assist the body in getting all of the nutrition out of the food for healing and restoring the body to normal function. Recently, an in vitro system was used to test the use of supplemental digestive enzymes. The digestive enzymes improved the digestibility and bioaccessibility of proteins and carbohydrates in the lumen of the small intestine, not only under impaired digestive conditions, but also in healthy human digestion [ 168 ].

There is evidence that indicates the presence of an enteropancreatic circulation of digestive enzymes [ 169 ]. Digestive enzymes appear to be preferentially absorbed into the bloodstream and then reaccumulated by the pancreas for use again. There appears to be a mechanism by which digestive enzymes can reach systemic circulation.

Enzymes, especially proteases, if they reach systemic circulation, can have direct anti-tumor activity. Wald et al [ 170 ] reported on the anti-metastatic effect of enzyme supplements. Mice inoculated with the Lewis lung carcinoma were treated with a proteolytic enzyme supplement, given rectally (to avoid digestion). The primary tumor was cut out, so that the metastatic spread of the cancer could be measured. After surgical removal of the primary tumor (day 0), 90% of the control mice died by day 18 due to metastasized tumors. In the first group, which received the rectal enzyme supplement from the time of the tumor-removal surgery, 30% of the mice had died from metastasized cancer by day 25. In the second group, which received the enzymes from 6 days prior to removal of the primary tumor, only 10% of the animals showed the metastatic process by day 15. In the third group, which received the enzyme treatment since the initial inoculation of the Lewis lung carcinoma, no metastatic spread of the tumor was discernible. One hundred day-survival rates for the control, first, second, and third groups were 0, 60%, 90%, and 100%.

In a similar experiment, an enzyme mixture of papain, trypsin, and chymotrypsin, as used in the preparation Wobe-Mugos E, was rectally given to mice that were inoculated with melanoma cells. Survival time was prolonged in the test group (38 days in the enzyme group compared to 24 days in the control mice) and 3 of the 10 enzyme-supplemented mice were cured. Again, a strong anti-metastatic effect of the proteolytic enzymes was seen [ 171 ].

Further evidence of the efficacy of oral enzyme supplementation is available from clinical trials in Europe. Two different studies have demonstrated that two different oral proteolytic enzyme supplements were able to reduce high levels of transforming growth factor-β, which may be a factor in some cancers [ 172 , 173 ]. In the Slovak Republic an oral enzyme supplement was tested in a placebo-controlled trial of multiple myeloma. For stage III multiple myeloma, control group survival was 47 months, compared to 83 months (a 3 year gain) for patients who took the oral enzymes for more than 6 months [ 174 ].

Enzyme supplements have also been shown to reduce side effects of cancer therapy. Enzyme supplementation resulted in fewer side effects for women undergoing radiation therapy for carcinomas of the uterine cervix [ 175 ], for patients undergoing radiation therapy for head and neck cancers [ 176 ], and for colorectal cancer patients undergoing conventional cancer treatments [ 177 ]. In a large multi-site study in Germany women undergoing conventional cancer therapy were put into a control group or a group that received an oral enzyme supplement. Disease and therapy related symptoms were all reduced, except tumor pain, by the enzyme supplement. Also, survival was longer with less recurrence and less metastases in the enzyme group [ 178 ]. In all of these studies the oral enzyme supplements were well tolerated, with only a small amount of mild to moderate gastrointestinal symptoms.

Even though these few studies don't give a lot of evidence of the effectiveness of oral enzyme supplementation, it is clear that there are some circumstances that will be helped by enzyme supplementation, with very little danger of negative side effects. At the least, enzymes will improve digestion and lessen the digestive burden on the body, leaving more reserves for disease eradication. However, as the research indicates, the effect may be much greater than that, with the potential for direct anti-tumor activity.

Whole Diet Studies

A diet-based cancer therapy, the Gerson Therapy, was used to treat melanoma cancer. The five-year survival rates from their therapy compared very favorably to conventional therapy reported in the medical literature, especially for more advanced stages of melanoma [ 179 ] (see Table ​ Table7 7 ).

Gerson Therapy for Melanoma [179].

An Italian cohort of 8,984 women was followed for an average of 9.5 years, with 207 incident cases of breast cancer during that time. Their diets were analyzed by patterns – salad vegetables (raw vegetables and olive oil), western (potatoes, red meat, eggs and butter), canteen (pasta and tomato sauce), and prudent (cooked vegetables, pulses, and fish). Only the salad vegetable diet pattern was associated with a significantly lower risk of breast cancer, about 35% lower. For women of normal weight (BMI <25) the salad vegetable pattern was even more protective, about a 61% decreased risk of breast cancer [ 180 ]. The overall dietary pattern does make a very significant difference.

In US-based studies the "prudent" diet has been shown to be protective for colon cancer, while the "western" diet has been shown to be detrimental. The "western" dietary pattern, with its higher intakes of red meat and processed meats, sweets and desserts, French fries, and refined grains, was associated with a 46% increase relative risk of colon cancer in the Nurses' Health Study [ 45 ]. Slattery et al [ 17 ] found a two-fold increase in relative risk of colon cancer associated with a "western" dietary pattern, and a 35–40% decrease in relative risk associated with the "prudent" pattern, especially among those diagnosed at an earlier age (<67 years old). The "salad vegetable" pattern is still more likely to be protective compared to the prudent dietary pattern, but this pattern did not exist in this study population.

In an analysis of the colon cancer data from the Health Professionals Follow-up Study, Platz et al [ 56 ] found that there was a 71% decrease in colon cancer risk when men with none of six established risk factors were compared to men with at least one of these risk factors (obesity, physical inactivity, alcohol consumption, early adulthood cigarette smoking, red meat consumption, and low intake of folic acid from supplements). So, if all men had the same health profile as these healthier 3% of the study population, colon cancer rates would have been only 29% of what they measured.

A plant-based dietary pattern in being currently tested in the Women's healthy Eating and Living (WHEL) Study. About 3,000 women who were treated for an early stage of breast cancer have been randomized into two groups. The dietary goals for the test group of the study are 5 servings of vegetables, 16 oz of vegetable juice, 3 servings of fruit, 30 g of fiber, and <20% of energy from fat. No guidelines were given for animal product intake, and initial results seem to confirm, since there were no changes in body weight, total cholesterol, or LDL cholesterol [ 181 ], which would be affected by animal protein intake. However, over the first year of follow-up vegetable intake did increase to seven servings/day, fruit intake increased to 3.9 servings/day, energy from fat decreased from 28% to 23%. Also, plasma carotenoid concentrations increased significantly in the intervention group, but not in the control group. α-Carotene increased 223%, β-carotene increased 87%, lutein increase 29%, and lycopene increased 17% [ 182 ], indicating that a substantial dietary change had been made by these women. It will be very interesting to follow the results of this study.

Conclusions

What is the result when all of these things are put together? What if all of these factors reviewed here were taken into account and put into practice? This anticancer diet would have:

• adequate, but not excessive calories,

• 10 or more servings of vegetables a day, including cruciferous and allium vegetables; vegetable juice could meet part of this goal,

• 4 or more servings of fruits a day,

• high in fiber,

• no refined sugar,

• no refined flour,

• low in total fat, but containing necessary essential fatty acids,

• no red meat,

• a balanced ratio of omega 3 and omega 6 fats and would include DHA,

• flax seed as a source of phytoestrogens,

• supplemented with ~200 μg/day selenium,

• supplemented with 1,000 μg/day methylcobalamin (B-12),

• very rich in folic acid (from dark green vegetables),

• adequate sunshine to get vitamin D, or use 1,000 IU/day supplement,

• very rich in antioxidants and phytochemicals from fruits and vegetables, including α-carotene, β-carotene, β-cryptoxanthin, vitamin C (from foods), vitamin E (from foods),

• very rich in chlorophyll,

• supplemented with beneficial probiotics,

• supplemented with oral enzymes

As reviewed above, reductions of 60 percent in breast cancer rates have already been seen in human diet studies, and a 71 percent reduction in colon cancer for men without the known modifiable risk factors. These reductions are without taking into account many of the other factors considered in this review, such as markedly increased fruit and vegetable intake, balanced omega 3 and 6 fats, vitamin D, reduced sugar intake, probiotics, and enzymes – factors which all are likely to have an impact on cancer. Certainly cancer prevention would be possible, and cancer reversal in some cases is quite likely.

Competing Interests

Michael Donaldson is a research scientist at the Hallelujah Acres Foundation, a foundation for investigations pertaining to the Hallelujah Diet. Funding for this review was provided by the Hallelujah Acres Foundation.

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  • NEWS FEATURE
  • 14 February 2024
  • Correction 15 February 2024

The future of precision cancer therapy might be to try everything

  • Elie Dolgin 0

Elie Dolgin is a science journalist in Somerville, Massachusetts.

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The blood cancer had returned, and Kevin Sander was running out of treatment options. A stem-cell transplant would offer the best chance for long-term survival, but to qualify for the procedure he would first need to reduce the extent of his tumour — a seemingly insurmountable goal, because successive treatments had all failed to keep the disease in check.

As a last throw of the dice, he joined a landmark clinical trial. Led by haematologist Philipp Staber at the Medical University of Vienna, the study is exploring an innovative treatment strategy in which drugs are tested on the patient’s own cancer cells, cultured outside the body.

In February 2022, researchers tried 130 compounds on cells grown from Sander’s cancer — essentially trying everything at their disposal to see what might work.

One option looked promising. It was a type of kinase inhibitor that is approved to treat thyroid cancer, but it is seldom, if ever, used for the rare subtype of lymphoma that Sander had. Physicians prescribed him a treatment regimen that included the drug, and it worked. The cancer receded, enabling him to undergo the stem-cell transplant. He has been in remission ever since. “I’m a bit more free now,” says Sander, a 38-year-old procurement manager living in Podersdorf am See, Austria. ”I do not fear death any more,” he adds. “I try to enjoy my life.”

His story is a testament to this kind of intensive and highly personalized drug-screening method, referred to as functional precision medicine. Like all precision medicine, it aims to match treatments to patients, but it differs from the genomics-guided paradigm that has come to dominate the field. Instead of relying on genetic data and the best available understanding of tumour biology to select a treatment, clinicians throw everything they’ve got at cancer cells in the laboratory and see what sticks.

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Is precision public health the future — or a contradiction?

But what it sometimes lacks in elegance, it could make up for in results: in pilot studies, Staber and his colleagues found that more than half of people with blood cancer whose treatment was guided by functional drug testing enjoyed longer periods of remission compared with their experiences of standard treatments 1 , 2 . Large-scale testing of genome-directed approaches suggests that the techniques are very effective against some cancers, yet they benefit, at most, only around 10% of patients overall 3 . Staber and his group’s latest trial is the first to compare functional- and genome-guided approaches head-to-head alongside treatments directed by standard pathology and physician intuition.

“That’ll be a very powerful study, and it will probably vindicate the utility of these functional assays,” says Anthony Letai, a haematologist at the Dana-Farber Cancer Institute in Boston, Massachusetts, and president of the Society for Functional Precision Medicine, a professional organization founded in 2017 to advance the field. And, if anecdotal reports serve as any indication, the try-everything tactic seems to bring about meaningful improvements, even when the genetic sequence of a tumour provides no actionable information, as was the case for Sander.

Companies around the world are already offering these kinds of personalized drug testing service. But proponents of the strategy still have much to prove. Although the concept of screening a bunch of drugs seems simple, the methods used to culture cancer cells outside the body can be technically demanding, time-consuming and costly.

The challenges are particularly acute for solid tumours, which live in complex environments inside the body; replicating those conditions is no easy feat. Researchers are trying wildly differing methods that range from growing tumour samples in mice and chicken embryos to cultivating carefully engineered organoids, and even the delivering infinitesimal amounts of various medicines to a tumour while it’s still in a patient.

Figuring out what works and what is practical, with regard to cost and scale, won’t be easy. But momentum is growing, says Christopher Kemp, a cancer biologist at the Fred Hutchinson Cancer Center in Seattle, Washington. “This is a revolution. Patients are demanding this approach.”

Behind the screen

Down a long corridor, beyond a set of tangerine-coloured doors, lies the Vivi-Bank at the Medical University of Vienna. Short for ‘Viable Biobank’, the room is brimming with liquid-nitrogen dewars, each containing frozen lymphoma samples.

When surgeons extract biopsies from cancerous lymph nodes, they usually immerse the tissue in formaldehyde to prepare for standard pathology analyses. That kills the cells, however, rendering them useless for functional testing. So, to enable drug screens, Staber and haematopathologist Ingrid Simonitsch-Klupp, who jointly oversee the Vivi-Bank, had to convince their surgical colleagues to change their ways, keeping the tissue alive and sending it quickly for processing and storage. “Fresh tissue is the most important thing,” Simonitsch-Klupp says.

Some of that tissue arrives in Staber’s lab, where researchers break up the cells using a knife, forceps and a nylon strainer, creating a slurry to distribute across a 384-well plate. In each well, they test a different drug compound — chemotherapy agents, enzyme-targeted drugs, immune-modulating therapies and more. After a night of incubation, lab testing reveals which drugs are active against the cancer and which ones are not.

A team of clinicians, known as a molecular tumour board, then uses this information to determine the most appropriate course of treatment for each patient.

Several groups have reported success with this general approach. In a trial from the University of Helsinki, for example, researchers found that individualized drug screening of leukaemia cells provided informative results substantially faster than did genomic profiling, yielding impressive clinical responses as well 4 . Of 29 people with treatment-resistant acute myeloid leukaemia (AML), 17 responded to drug-screening-informed therapies and entered remission.

Likewise, Candace Howard, a radiologist at the University of Mississippi Medical Center in Jackson, and her colleagues published a study last year showing that people with aggressive brain tumours live longer when their chemotherapy regimens are guided by lab testing than when their treatment is directed by a physician’s intuition alone 5 — with lower annual health-care costs to boot 6 .

A plate containing different cancer drugs and a graphical drug sensitivity testing result output

Multi-well plates can be used to test the effectiveness of many cancer drugs at once. Credit: FIMM, University of Helsinki

“It’s cheaper and it’s more effective,” says Jagan Valluri, a cell biologist at Marshall University in Huntington, West Virginia, who co-founded a company called Cordgenics, also based in Huntington, to commercialize the assay used in Howard’s trial.

Functional drug testing is not a new idea. It was embraced by cancer researchers in the late twentieth century, but soon fell out of favour — largely owing to the limitations of assays at the time and a restricted repertoire of anti-cancer drugs. Technological improvements and an expanded pharmacopoeia have changed the picture. Yet, as with most lab-based testing systems, the necessary equipment can be expensive and requires trained personnel to operate it.

That’s a big limitation according to Joan Montero, a biochemist at the University of Barcelona in Spain, because it hinders the broad implementation of functional precision drug testing, especially in low-resource settings. To address these challenges, Montero and his colleagues have been developing inexpensive and portable microfluidic devices for rapid, on-site testing of cancer cells 7 .

Their microfluidic platform remains years away from practical use, however. And it might guide treatment only for certain types of cancer. That’s because protocols developed for tailoring therapies against blood cancers do not always work in solid tumours of the breast, lung, liver and other organ systems.

Biopsies from solid tumours often yield lower cell counts, requiring extra steps to culture the cells before drug screening. Moreover, solid tumours have complex interactions with healthy cells in their surroundings, meaning that models should be more sophisticated.

Growing pains

The first challenge remains growing enough tumour tissue to test. David Ziegler, a paediatric neuro-oncologist at Sydney Children’s Hospital in Australia, had set out to perform individualized drug screens for around 1,000 children with high-risk cancers as part of the country’s Zero Childhood Cancer Program. But in pilot testing, he and his team discovered that, after several days under lab conditions, up to one-fifth of the patient samples either contained no cancer cells at all, or the cancer cells were being outcompeted by normal, healthy cells 8 . The researchers quickly learnt to check cultures for tumour cells — through imaging, cellular analysis or genetic profiling — before testing them against drugs.

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Super-precise CRISPR tool enters US clinical trials for the first time

Cell cultures from solid tumours can, in principle, be subjected to the same kind of testing used for blood cancers. But an increasing number of research teams are crafting elaborate structures, known as organoids , to test. These patient-derived 3D tissue models — made by growing tumour samples in specialized scaffolds over the course of several weeks — are designed to replicate the intricate tissue architecture of a tumour, thereby offering a more accurate representation of the cancer that physicians are looking to treat.

“We want to put the tumour cells in an environment that’s as close [as possible] to how they were growing in the body,” says Alice Soragni, a cancer biologist at the University of California, Los Angeles.

The process can add weeks to the timeline for obtaining drug sensitivity data. But the extra effort and time investment is worth it, says Carla Grandori, co-founder and chief executive of SEngine Precision Medicine in Bothell, Washington.

In clinical validation studies, Grandori and her SEngine colleagues found that the drug-screening results using organoids aligned with patient outcomes with around 80% accuracy. Those findings are not yet published, but the company — which counts Kemp among its founders — has put out case reports over the past year describing people with difficult-to-treat cancers who, after seemingly running out of treatment options, found unexpectedly effective remedies through organoid drug testing 9 , 10 .

Heidi Gray, a gynaecological oncologist at the University of Washington Medical Center in Seattle, treated one of these patients, a woman with ovarian cancer. “Her response was definitely one of the best I’ve seen,” she says. The drug they tried is generally used to treat leukaemia, but it helped to beat back the woman’s ovarian tumour for more than a year, allowing her to travel and enjoy precious time with loved ones before ultimately succumbing to the disease. “We profoundly improved her quality of life,” Gray says, “and that would not have happened without the knowledge provided by this test.”

Model of efficiency

In the hope of testing drugs against even more realistic cancer systems, some researchers have opted to study mice implanted with fresh tumour specimens, a model system known as a patient-derived xenograft .

These personalized ‘avatars’ were once heralded as the next big thing in cancer care. But it soon became evident that many tumours do not grow in mice, that drug screening in xenografts takes too long to provide timely recommendations and that the cost of the approach — often exceeding US$50,000 — is more than most patients and health-care systems can bear.

“It was too slow, too expensive and not robust enough,” says David Sidransky, an oncologist at Johns Hopkins University School of Medicine in Baltimore, Maryland, and a co-founder of Champions Oncology, a leading developer of xenograft models, based in Hackensack, New Jersey.

Albert Manzano and Joan Montero work at a fume hood on a microfluidic device used to predict cancer therapy response

Joan Montero (standing) and his colleagues are developing a low-cost microfluidic device. Credit: University of Barcelona

Although some drug companies continue to use xenografts for research, and some oncologists think that there are certain situations in which they can inform patient care, for the most part, researchers have moved away from mice for functional testing in the clinic. Some have moved on to other living systems.

One such alternative comes from cancer biologist Hon Leong and his colleagues at Sunnybrook Hospital in Toronto, Canada, who devised a system for screening drugs on tumour biopsy samples cultivated on developing chicken embryos. The approach is both rapid and inexpensive, says Leong, allowing researchers to assess different drug options in a matter of weeks rather than the months required for mice.

In ongoing trials focused on advanced breast and kidney cancers that have spread to other parts of the body, Leong and his team have successfully used the chicken-embryo system to identify individuals who would benefit from immune therapies. These are among the most effective cancer treatments today, and a drug class that few other avatar systems can accurately assess, says Leong.

scientific paper about cancer

CRISPR cancer trial success paves the way for personalized treatments

Another approach comes from Ross Cagan, a developmental biologist at the University of Glasgow, UK, who uses genomic sequencing and genetic engineering to recreate the unique characteristics of a patient’s tumour in a custom-made fruit fly. This involves introducing mutated forms of cancer-promoting genes or incorporating sequences that restrict cancer-suppressing genes — generally between 5 and 16 alterations in total. Feeding the flies with food containing various medications can then reveal therapeutic regimens that suppress cancer growth, either by acting directly on tumour cells or by influencing the animal’s biology in ways that indirectly impede cancer progression.

This is how Cagan and his colleagues identified a new three-drug cocktail — consisting of a lymphoma treatment, a blood-pressure medicine and an arthritis therapy — that, when administered to a man with a rare tumour of the salivary glands, helped to stabilize the cancer for a year 11 . In another case, involving a man with an aggressive form of colon cancer, the use of fly avatars guided the team to administer a melanoma drug alongside a bone-strengthening agent, resulting in notable tumour shrinkage and a clinical response that lasted for nearly a year 12 . A biotech start-up in London called Vivan Therapeutics now offers this bespoke fly-making and drug-screening service for $15,000 per patient.

Close up of chicken embryos in blue plastic trays which are prepared for growing cancer tumors

A researcher prepares developing chicken embryos to grow model tumours. Credit: Hon Sing Leong

Any model invariably has biological limitations, however, and so some researchers have elected to do away with animal stand-ins or cellular replicas entirely. Instead, they have developed implantable devices that allow clinicians to test drugs directly on patient tumours — and to do so while the cancer is still inside the body.

Last year, bioengineer Oliver Jonas at Brigham and Women’s Hospital in Boston, and his colleagues demonstrated the feasibility of this strategy in people with lung 13 and brain 14 cancers. In small trials, surgeons inserted tiny drug-releasing devices, each loaded with nanodoses of up to 12 drugs, into tumours as people underwent cancer-removal surgery. Over the course of the operation, drugs flowed into the surrounding tissue from separate reservoirs in a device the size of a grain of rice.

Those tissues, along with the device itself, were then removed at the end of the procedure, and subsequently inspected for molecular indicators of drug action. So far, the data collected haven’t been used to guide treatments, but retrospective analyses hinted at potential benefits if they had. Two companies — Boston-based Kibur Medical, co-founded by Jonas, and Presage Biosciences, headquartered in Seattle — are now developing these kinds of in situ drug-testing platform.

A choice opportunity

An assay’s treatment predictions are only as good as a patient’s ability to access the recommended drugs — and, when those are expensive cancer agents that have not been approved for the desired use, costs and insurance reimbursement can be impediments.

Pamela Becker, a haematologist at City of Hope cancer centre in Duarte, California, has encountered some of these problems when trying to prescribe drugs that were identified during assay-guided treatment trials for people with multiple myeloma and other blood cancers. “I couldn’t get my top choice,” she says. Becker had to go down the list of recommendations, eventually finding drugs that would be covered by insurance.

scientific paper about cancer

The mice with human tumours: Growing pains for a popular cancer model

Another financial obstacle remains reimbursement for the functional tests themselves. In the United States, an official policy enacted in 1996 classifies drug-sensitivity assays as ‘experimental’, making them ineligible for coverage under Medicare, the federal government’s giant health insurance programme for older people. Changing reimbursement rules will thus require reversing that decades-old decision, says Bruce Yeager, an independent consultant in functional precision diagnostics based in Johns Creek, Georgia — an extra hurdle that means “we’re not starting from a point of neutrality”, he says. “We’re starting from negativity.”

Combating such policies and entrenched practices hinges on the availability of compelling clinical data. But accumulating such data can be challenging when the medical establishment is not geared towards enabling functional drug testing. It’s something of a catch-22, says Letai. “But that cycle is going to break in the next couple of years,” he says, “and then I think you’re going to see a sort of non-linear adoption of these strategies, because the power and the need for them is so great.”

Functional testing strategies might even work for conditions outside the cancer arena. In cystic fibrosis, for example, organoid models made from rectal or intestinal tissue are beginning to help clinicians to find effective drug regimens for people with rare disease-causing mutations who are not eligible to receive any approved treatments. “It just makes a lot of sense,” says Jeffrey Beekman, a cystic-fibrosis researcher at the University Medical Center Utrecht in the Netherlands, who has pioneered the approach.

Many cancer researchers feel the same way, and now they just need to prove it to the wider medical community. All eyes are therefore on Staber and his randomized trial, which researchers anticipate will go a long way towards convincing clinicians that genomics is not the be-all and end-all of personalized care. “Paradigm shifts can be very threatening to people,” says Howard, the University of Mississippi radiologist, “but it shouldn’t be threatening. It’s just another tool in our arsenal against disease.”

Nature 626 , 470-473 (2024)

doi: https://doi.org/10.1038/d41586-024-00392-2

Updates & Corrections

Correction 15 February 2024 : An earlier version of this feature stated that Philipp Staber’s lab uses a 386-well plate.

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    DOI: 10.1353/pbm.2019.0046 Abstract This essay focuses on themes in Explaining Cancer: Finding Order in Disorder (2018) by Anya Plutynski, a monograph that has important things to say about both the peculiarities of cancers and our theories about them.

  18. Cancers

    Cancers is a peer-reviewed, open access journal of oncology, published semimonthly online by MDPI.The Irish Association for Cancer Research (IACR), Spanish Association for Cancer Research (ASEICA), Biomedical Research Centre (CIBM), British Neuro-Oncology Society (BNOS) and Spanish Group for Cancer Immuno-Biotherapy (GÉTICA) are affiliated with Cancers and their members receive a discount on ...

  19. Articles

    Window-of-opportunity (WOO) studies provide insights into the clinical activity of new drugs in breast cancer. Mario Campone, François-Clément Bidard, Patrick Neven, Lei Wang, Bin Ling, Yvonne Dong, Gautier Paux, Christina Herold and Ugo De Giorgi. Breast Cancer Research 2023 25 :141.

  20. Innovative approaches for cancer treatment: current perspectives and

    Extracellular vesicles for cancer diagnosis and therapy. EVs are classified in two categories based on their biogenesis. Specifically, exosomes are small vesicles of around 30-150 nm originated from endosomes in physiological and pathological conditions and released by a fusion of multivesicular bodies (MVBs) to the cell membrane [55, 56], while shed microvesicles (sMVs), with a typical size ...

  21. Researchers characterize the immune landscape in cancer

    Researchers have unveiled a detailed understanding of immune responses in cancer, marking a significant development in the field. Utilizing data from more than 1,000 tumors across 10 different ...

  22. Cancer keeps coming for the young. Why?

    A report released last month by the American Cancer Society reflects significant progress in recent decades in early detection and treatment of the disease. That's the good news. The report also highlights a disturbing new development: Higher rates of colorectal cancer among younger people. Kimmie Ng, an associate professor of medicine at Harvard Medical School and the founding director of ...

  23. The neuroscience of cancer

    Abstract. The nervous system regulates tissue stem and precursor populations throughout life. Parallel to roles in development, the nervous system is emerging as a critical regulator of cancer ...

  24. Why age matters when it comes to cancer

    Luca Magnani, an epigeneticist at the Institute of Cancer Research in the UK, says that this is a working theory for breast cancer, potentially triggered by the hormonal changes which begin in ...

  25. The Scandals Rocking Cancer Science Matter to Your Health

    The field of cancer biology is a mess. Signs of trouble emerged years before the most recent scandal, in which investigators found evidence of data manipulation in a slew of high-profile papers ...

  26. Science sleuths are using technology to find fakery and plagiarism in

    The blog post included problems spotted by David and others previously exposed by sleuths on PubPeer, a site that allows anonymous comments on scientific papers.. Student journalists at The Harvard Crimson covered the story on Jan. 12, followed by reports in other news media. Sharpening the attention was the recent plagiarism investigation involving former Harvard president Claudine Gay, who ...

  27. Nutrition and cancer: A review of the evidence for an anti-cancer diet

    It has been estimated by the American Institute for Cancer Research and the World Cancer Research Fund that 30-40 percent of all cancers can be prevented by appropriate diets, physical activity, and maintenance of appropriate body weight [ 1 ]. It is likely to be higher than this for some individual cancers.

  28. Chinese team tests lung treatment that may be first to reverse damage

    Paper follows statement by Zuo Wei that 'stem cell and progenitor cell-based regenerative medicine may be the biggest, if not the only, hope to cure COPD' During a six-minute walking test, the ...

  29. The future of precision cancer therapy might be to try everything

    The blood cancer had returned, and Kevin Sander was running out of treatment options. A stem-cell transplant would offer the best chance for long-term survival, but to qualify for the procedure he ...