Preclinical Study Finds Cancer Stem Cell Inhibitor Sensitizes Colon Cancer Cells To Immunotherapy

MedicalResearch.com Interview with:
Dr. Yuan Gao

Assistant Investigator at Boston Biomedical

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Colorectal cancer (CRC) is the third most commonly diagnosed malignant disease and third most frequent cause of cancer-related death in the United States. Standard treatment for unresectable metastatic CRC currently includes first and second line 5-fluorouracil (5-FU)-based chemotherapy regimens. However, CRC patients often develop chemoresistance. Recently, immunotherapy has emerged as a revolutionary new treatment for CRC. However, with the exception of a small percentage of CRC patients that display microsatellite instability (MSI), the vast majority of colorectal cancer patients have been found to be resistant to immune checkpoint therapies.

Cancer stem cells (CSCs), a highly malignant tumor cell subpopulation capable of self-renewal, are considered to be fundamentally responsible for malignant growth and tumor recurrence. Emerging evidence indicates that CSCs and cancer stemness pathways, such as STAT3, beta-Catenin, CD44 and Nanog, are involved in the immune evasion of cancers. BBI-608 (napabucasin) is an orally-administered first-in-class cancer stemness inhibitor that works by targeting STAT3. In this study, we investigated the effect of cancer stemness inhibition on sensitizing colorectal cancer to immune checkpoint inhibitors in preclinical models.

In the syngeneic microsatellite stable (MSS) tumor model, CT26, an anti-PD-1 antibody delivered as a monotherapy, produced low level and temporary antitumor activity with rapid development of complete resistance to anti-PD-1 treatment. The anti-PD-1 antibody-treated CT26 tumors exhibited increased p-STAT3 activation and overexpression of a variety of stemness factors, as well as enrichment of sphere-forming stemness-high cancer cells. Napabucasin was able to reduce basal as well as anti-PD1-induced STAT3 activation and other CSC features within CT26 tumors. The combination of a stemness inhibitor – napabucasin – with the anti-PD-1 antibody led to tumor complete response (CR) in all treated CT26 tumors, with 40 percent of the mice remaining tumor-free for 30 days following treatment termination. This combination also had a synergistic effect on the influx of tumor infiltrating CD8+ T cells, which likely contributed to the rapid tumor regression. Finally, mice CR-induced by napabucasin and the anti-PD-1 antibody were able to reject CT26 tumors upon re-challenge, but not the unrelated breast cancer 4T1 tumors.

MedicalResearch.com: What should readers take away from your report?

Response: Our data suggest cancer stemness pathways contribute to immunotherapy resistance in MSS CRC, a subtype representing the vast majority of colorectal cancer cases. Furthermore, inhibition of cancer stemness by BBI-608 sensitizes colorectal cancer to immune checkpoint inhibition, producing striking regression in a large proportion of the tumors treated.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: This study provides compelling preclinical evidence to support the investigation of the combination of napabucasin with immune checkpoint inhibitors in CRC. While this study specifically investigated the combination with anti-PD-1, the combination with other immunotherapies could be studied as well.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation: AACR 2017 Abstract

Inhibition of cancer stemness sensitizes colorectal cancer to immune checkpoint inhibitors
Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Colorectal Cancer Risk Model Using Environmental and Genetic Factors

MedicalResearch.com Interview with:

Victor Moreno, PhD. Director of Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain Department of Clinical Sciences, Faculty of Medicine University of Barcelona Barcelona, Spain

Dr. Moreno

Victor Moreno, PhD.
Director of Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain
Department of Clinical Sciences, Faculty of Medicine
University of Barcelona
Barcelona, Spain

Gemma Ibáñez-Sanz, MD Gastroenterologist. *Cancer Prevention and Control Unit, Catalan Institute of Oncology. L’Hospitalet deLlobregat, Barcelona, SPAIN *Gastroenterology Department, Bellvitge University Hospital-IDIBELL,  L’Hospitalet de Llobregat, Spain

Dr. Ibáñez-Sanz

Gemma Ibáñez-Sanz, MD
Gastroenterologist.
*Cancer Prevention and Control Unit, Catalan Institute of Oncology. L’Hospitalet deLlobregat, Barcelona, SPAIN
*Gastroenterology Department, Bellvitge University Hospital-IDIBELL,
L’Hospitalet de Llobregat, Spain 

MedicalResearch.com: What is the background for this study?

Response: Colorectal cancer (CRC) screening by faecal occult blood testing has been demonstrated to reduce CRC incidence and mortality, as well as being a cost-effective strategy compared to no screening. Currently, the target population is defined basically by age (≥50 years old), which has been called a ‘one-size-fits-all’ strategy. This strategy implies performing unnecessary screening tests in low-risk people leading to avoidable risks for patients and extra costs for the healthcare system. On the other hand, high-risk patients may receive non-invasive testing, which is a suboptimal screening technique in their case. Several risk prediction models, either for  colorectal cancer or advanced neoplasia, have been previously developed, all with limited discriminating ability.

We have developed a risk stratification model that combines environmental factors with family history and genetic susceptibility. Furthermore, we have assessed the relative contribution of these factors and the utility of the model for risk stratification and public health intervention.

MedicalResearch.com: What are the main findings?

Response: Data from common genetic susceptibility loci could be useful to stratify colorectal cancer screening in average-risk population. Individuals in the top quintile of risk alleles have an 82% increased risk compared to those in the lower quintile. We have estimated the impact of determining an individual environmental and genetic risk score in a Spanish CRC screening population. In our model, although the genetic factors are significant contributors, the modifiable risk factors contribute more strongly. Risk assessment may increase screening participation and adoption of healthier lifestyles.

MedicalResearch.com: What should readers take away from your report?

Response: On average, each environmental risk factor increases CRC risk by 35%, while each risk allele only increases it by 7%. This implies that the change of one modifiable risk factor towards healthier lifestyle might offset the effect of 4 risk alleles. Given the fact that environmental factors explain part of the CRC risk, we believe it to be important to give thought to incorporating clinical data to encourage individuals to achieve a healthier lifestyle. As the European Code Against Cancer recommends, and our findings confirm, one should have a healthy diet, a healthy body weight, be physically active and should not smoke or a high consumption of alcohol.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: Future prospective studies should aim to analyse if stratifying by genetic and lifestyle risk scores is useful and cost-effective to improve screening. Subjects with higher predicted risk should probably start screening earlier and decrease the intervals between tests, while low risk individuals could start later or space more the between test intervals.

MedicalResearch.com: Is there anything else you would like to add? 

Response: Population acceptability of genetic tests is not well known. We are currently recruiting subjects from colorectal cancer screening and gastroenterology clinics in a study called COLSCREEN to assess risk perception and attitudes regarding genetic testing to prevent cancer.

No disclosures

Citation:

Sci Rep. 2017 Feb 24;7:43263. doi: 10.1038/srep43263.

Risk Model for Colorectal Cancer in Spanish Population Using Environmental and Genetic Factors: Results from the MCC-Spain study.

Ibáñez-Sanz G1, Díez-Villanueva A1, Alonso MH1,2, Rodríguez-Moranta F2,3, Pérez-Gómez B2,4,5, Bustamante M2,6, Martin V2,7, Llorca J2,8, Amiano P2,9, Ardanaz E2,10, Tardón A2,11, Jiménez-Moleón JJ2,12, Peiró R2,13, Alguacil J2,14, Navarro C2,15, Guinó E1,2, Binefa G1,2, Navarro PF2,4,5, Espinosa A2,6, Dávila-Batista V7, Molina AJ2,7, Palazuelos C8, Castaño-Vinyals G2,6,16,17, Aragonés N2,4,5, Kogevinas M2,6,16,17,18, Pollán M2,4,5, Moreno V1,2,19.

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Colon Cancer Incidence Rises Dramatically For Young People in Their 20s and 30s

MedicalResearch.com Interview with:
Rebecca L. Siegel, MPH

Surveillance and Health Services Research
American Cancer Society
Atlanta, GA 

MedicalResearch.com: What are the main findings?

Response: It was known that colorectal cancer incidence rates are declining rapidly in people 50 years and older, but curiously increasing in people younger than 50 years. For a more comprehensive understanding of incidence patterns, we examined CRC incidence trends by 5-year age group and year of birth using age-period cohort analysis. This modeling technique helps enhance the understanding of disease trends by disentangling factors that influence all ages (period effects) from those that vary by generation (birth cohort effects).

In incidence data for almost 500,000  colorectal cancer patients during 1974-2013, we found both period and cohort effects. However, the period effects were dwarfed by the cohort effects. The age-specific risk of colorectal cancer declined during the first half of the 20thcentury, but has increased for subsequent generations since around 1950, such that those born in 1990 have twice the risk of colon cancer and 4 times the risk of rectal cancer compared to people born in 1950. Said another way, someone in their 20s today is 4 times more likely to be diagnosed with rectal cancer than someone who was in their 20s in 1970. The risk for contemporary generations has escalated back to that of people born circa 1890.

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Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer

MedicalResearch.com Interview with:
Matthew B Yurgelun, M.D

Instructor in Medicine, Harvard Medical School
Dana-Farber Cancer Institute

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: It has long been known that hereditary factors play a key role in colorectal cancer risk. It is currently well-established that approximately 3% of all colorectal cancers arise in the setting of Lynch syndrome, a relatively common inherited syndrome that markedly increases one’s lifetime risk of colorectal cancer, as well as cancers of the uterus, ovaries, stomach, small intestine, urinary tract, pancreas, and other malignancies. Current standard-of-care in the field is to test all colorectal cancer specimens for mismatch repair deficiency, which is a very reliable means of screening for Lynch syndrome. The prevalence of other hereditary syndromes among patients with colorectal cancer has not been known, though other such factors have been presumed to be quite rare.

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Stool DNA Tests (Cologuard ) Increases Colon Cancer Screening and Detection Among Previously Noncompliant Patients

MedicalResearch.com Interview with:

Dr. Mark Prince MD USMD Health System Arlington, TX 76017

Dr. Mark Prince

Dr. Mark Prince MD
USMD Health System
Arlington, TX 76017

MedicalResearch.com: What is the background for this study?

Response: This 12-month retrospective study conducted to determine the screening compliance rates for a noninvasive multitarget stool DNA (mt-sDNA) screening test (Cologuard) for colon cancer among a cohort of nearly 400 average-risk Medicare patients who had previously not complied with recommended screening. These were patients who had never had a colonoscopy, had been more than ten years since last colonoscopy, or had been more than one year since last stool testing for occult blood.

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Younger Colon Cancer Patients Receive More Chemotherapy But No Greater Survival Benefit

MedicalResearch.com Interview with:
Kangmin Zhu, PhD, MD

John P. Murtha Cancer Center, Walter Reed National Military Medical Center
Professor at the Uniformed Services University of the Health Sciences in the
Department of Preventive Medicine and Biostatistics
Bethesda, Maryland

MedicalResearch.com: What is the background for this study?

Response: An article published on JAMA Surgery in 2015 showed more utilization of chemotherapy among young colon cancer patients.  To demonstrate the study findings, we analyzed the data from the Department of Defense healthcare system, in which all members have the same level of access to medical care and therefore the potential effects of insurance status and types on research results can be reduced.

MedicalResearch.com: What are the main findings?

Response: The main findings were that young and middle-aged colon cancer patients were 2 to 8 times more likely to receive postoperative chemotherapy and 2.5 times more likely to receive multiagent regimens, compared with their counterparts aged 65 to 75 years.  However, no matched survival benefits were observed for the young and middle-aged among patients who received surgery and postoperative chemotherapy.

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Cancer Susceptibility Genes Common In Early-Onset Colorectal Cancer

MedicalResearch.com Interview with:

Heather Hampel, MS, LGC Associate Director, Division of Human Genetics Associate Director, Biospecimen Research Professor, Internal Medicine Licensed Genetic Counselor The Ohio State University Comprehensive Cancer Center Columbus, OH 43221

Heather Hampel

Heather Hampel, MS, LGC
Associate Director, Division of Human Genetics
Associate Director, Biospecimen Research
Professor, Internal Medicine
Licensed Genetic Counselor
The Ohio State University Comprehensive Cancer Center
Columbus, OH 43221

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This study was part of the Ohio Colorectal Cancer Prevention Initiative, a statewide study being conducted at 50 hospitals that includes universal tumor screening for Lynch syndrome. For the subset of 450 colorectal cancer patients diagnosed under age 50, we performed multi-gene cancer panel testing regardless of the results of their tumor screening for Lynch syndrome since early age of diagnosis is a red flag that a cancer might be hereditary.

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Screening for Colorectal Cancer Issues Evolve For Patients and Physicians

MedicalResearch.com Interview with:

David Lieberman MD Professor of Medicine Chief, Division of Gastroenterology and Hepatology Oregon Health and Science University L461 Portland, OR 97239

Dr. David Lieberman

David Lieberman MD
Professor of Medicine
Chief, Division of Gastroenterology and Hepatology
Oregon Health and Science University
Portland, OR 97239

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: New guidelines for colorectal cancer (CRC) screening from the USPSTF were published in June 2016. They recommended any of 8 different screening programs.

The purpose of this review was to highlight elements not included in the USPSTF report:
1. Elements of informed decision making associated with each program
2. Quality metrics for each program
3. Recommendations for higher than average risk individuals

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How Does Gout Affect Risk of Colon Cancer?

MedicalResearch.com Interview with:

Michael Pillinger, MD Professor of Medicine and Biochemistry and Molecular Pharmacology NYU School of Medicine

Dr. Michael Pillinger

Michael Pillinger, MD
Professor of Medicine and Biochemistry and Molecular Pharmacology
NYU School of Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We are interested in the co-morbidities of gout and the fact that gout is accompanied by multiple cardiovascular, renal and other events. The implications of gout for cancer are less clear, but the basic biology suggests that either:

1) the acute and chronic inflammation of gout could contribute to a pro-cancer environment;
2) the anti-oxidant effects of urate could have anti-cancer properties;
3) the ability of uric acid to serve as a “danger signal” released from dying cells (potentially including cancer cells” could promote anti-cancer immunity.

The clinical literature is murky at best.

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Prognostic Survival Associated With Left vs Right-Sided Colon Cancer

MedicalResearch.com Interview with:
Fausto Petrelli, MD
Oncology Unit, Oncology Department
Treviglio ,Italy

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This meta-analysis evaluated if side (excluding rectum site) represents an independent prognostic factor for survival in patients with stages 1-4 colon cancer. This variable is in fact associated with an adverse outcome with a reduced risk of death by 20% if patients are affected by a left colon cancer compared to those with right colon cancers. Implications are enormous: for prognosis first but also for follow-up, stratification into clinical trials and treatment (for both medical and surgical therapies). The power of the study is relevant: it enclosed 66 studies with more than 1 million of patients retrospectively or prospectively analyzed for survival according to common variables known to be prognostic in colorectal cancer (age, sex, stage, race, adjuvant CT..etc) in multivariate analysis.

Side is significantly associated with survival independent of other covariates analyzed. The question of the side is old and partially known, but no study systematically explored the published literature to confirm this suggestion. Recent large randomized trials in metastatic disease showed different results according to the site of disease with right colon cancers usually less responsive to anti-EGFR treatment due to a different molecular behavior and conversely left colon cancers which attained the greater benefit from cetuximab and panitumumab due to less BRAF mutations in their tissue. Also, a less extensive and radical lymphadenectomy in right-sided cancers, without a complete mesocolon excision during surgery, could hamper their cure rate, as our colorectal surgeon’s team lead by Prof. Giovanni Sgroi and Luca Turati MD, suggested in the discussion. It is also well known the leads term bias with a later diagnosis of right cancers due to clinical and anatomic reasons.

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Study Supports Routine Colon Cancer Screening Through Age 75, With Individualized Decisions Afterwards

MedicalResearch.com Interview with:

Xabier Garcia-De-Albeniz MD PhD Research Associate Department of Epidemiology Mongan Institute for Health Policy, Massachusetts General Hospital. Board Member, GEMCAD. Member, Group for Cancer Prevention, SEOM

Dr. Xabier Garcia-De-Albeniz

Xabier Garcia-De-Albeniz MD PhD
Research Associate
Department of Epidemiology
Harvard T.H. Chan School of Public Health
Mongan Institute for Health Policy
Massachusetts General Hospital

MedicalResearch.com: What is the background for this study?

Response: Randomized controlled trials are considered the gold standard to inform health care delivery. Unfortunately, no randomized controlled trials of screening colonoscopy have been completed. Ongoing trials exclude persons aged 75 or older, and will not have mature results before 2025. However, healthy persons older than 75 may live long enough to benefit from colorectal cancer (CRC) screening. The Medicare program reimburses screening colonoscopy without an upper age limit since the year 2001. We used the extensive experience of Medicare beneficiaries to evaluate the effectiveness and safety of screening colonoscopy.

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Circulating Tumor DNA Predicts Colon Cancer Relapse

MedicalResearch.com Interview with:

Jeanne Tie MBChB, FRACP, MD Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research Department of Medical Oncology, Western Health, St Albans, Victoria, Australia. Department of Medical Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne Parkville, Victoria, Australia

Dr. Jeanne Tie

Jeanne Tie MBChB, FRACP, MD
Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research
Department of Medical Oncology, Western Health, St Albans, Victoria, Australia.
Department of Medical Oncology,
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
Parkville, Victoria, Australia

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This study investigated the ability of circulating tumor DNA (ctDNA) in detecting residual microscopic cancer after surgery with curative intent in patients with stage II colon cancer. Although the majority of patients with stage II colon cancer are cured by surgery alone, our ability to accurately predict the risk of cancer relapse based on current clinical and pathological criteria is imprecise. Population-based study indicated that adjuvant chemotherapy is given to up to 40% of stage II colon cancer patients, meaning that we are over-treating a significant number of patients with cytotoxic therapy. A better indicator of residual disease and recurrence would be very useful clinically.

The current study collected tumor and blood samples from 230 patients with stage II colorectal cancer. A personalised assay was then designed to detect patient-specific tumor DNA in the plasma samples collected four to ten weeks after surgery. The presence of ctDNA (positive test) in the post-operative blood sample predicted recurrence in 100% of patients, while the relapse rate is only 10% in those with negative ctDNA test. We have also shown that the ctDNA test is a better predictor of recurrence than the standard clinic-pathological criteria.

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Vanderbilt Free Colonoscopies For Uninsured Detected Some Early Cancers and Was Cost Neutral

MedicalResearch.com Interview with:
Erica R. H. Sutton, MD
Assistant Professor
Department of Surgery, General
Vanderbilt

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Colorectal cancer is one of the most preventable diseases that we face; however, despite the great strides that we have made in the realm of early detection, many people still do not undergo screenings. We sought to increase the availability of screenings to those in our community who are at high risk for colorectal cancer and uninsured by providing free colonoscopies to them and to examine the cost-effectiveness of this intervention. Over a 12-month period, 682 uninsured people underwent screening colonoscopies, and 9 cancers were detected. Compared to the Surveillance, Epidemiology, and End Results (SEER) registry, our patient population included more early-stage cancers, and our program was found to be cost-neutral.

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Many Elderly Patients Not Receiving Adequate Colon Cancer Screening or Follow Up

MedicalResearch.com Interview with:

Carrie N. Klabunde, PhD Office of Disease Prevention Office of the Director NIH Rockville MD

Dr. Carrie Klabunde

Carrie N. Klabunde, PhD
Office of Disease Prevention
Office of the Director
NIH
Rockville MD

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Many studies of colorectal cancer screening focus on adults 50-75 years of age; few specifically look at screening in the elderly. We wanted to examine colorectal cancer screening use, including follow-up diagnostic testing for those with abnormal fecal blood screening tests, in adults 65 years of age and older. We also wanted to assess whether screening use in this population is influenced more by elderly individual’s chronological age, or their health status (called comorbidity in our study). The study was conducted in three large, integrated healthcare systems: Kaiser Permanente in Northern California and Southern California, and Group Health in Washington state and Idaho. We examined data on nearly 850,000 patients aged 65-89.

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Study Reevaluates Colon Cancer Screening Methods

MedicalResearch.com Interview with:
Jennifer S. Lin, MD, MCR, FACP
Director, Kaiser Permanente Research Affiliates Evidence-based Practice Center
Investigator, The Center for Health Research, Kaiser Permanente Northwest
Portland, OR 97227

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Lin: Our systematic review was commissioned by the USPSTF, in tandem with a separate modeling exercise, to help update their 2008 colorectal cancer screening recommendations. Since the previous recommendation, there has been a wealth of new evidence, including more evidence on the long-term effectiveness of flexible sigmoidoscopy for reducing colorectal cancer mortality, the screening accuracy and decreasing radiation exposure from CT colonography, and the screening accuracy for a number FDA-approved stool tests using fecal immunochemical testing (FIT).

While we have large, well-designed RCTs demonstrating that screening for colorectal cancer using flexible sigmoidoscopy and older generation stool testing reduces colorectal cancer mortality, these screening tests are no longer widely used in the United States. Well-designed diagnostic accuracy studies of screening colonoscopy, CT colonography, and various stool based tests using FIT demonstrate adequate sensitivity and specificity to detect adenomas and/or colorectal cancer, making each of them viable screening options. However, each screening option has potential harms associated with their use, particularly those allowing for direct visualization of the colon. Colonoscopy harms include perforations and major bleeding events. CT colonography requires exposure to radiation; and CT colonography not uncommonly results in detection of extra-colonic findings which necessitate additional diagnostic follow-up which may result in a benefit or harm.
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Germline Mutation Predicts Response To Cetuximab in Colon Cancer

MedicalResearch.com Interview with:

Dr. Geoffrey Liu, MD MSC Princess Margaret Hospital/Ontario Cancer Institute University of Toronto Toronto, Ontario Canada

Dr. Geoffrey Liu

Dr. Geoffrey Liu, MD MSC
Princess Margaret Hospital/Ontario Cancer Institute
University of Toronto
Toronto, Ontario
Canada

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Liu: Cetuximab is a monoclonal antibody therapy used in metastatic colorectal cancer patients when other chemotherapy options have been exhausted. Currently, the only useful biomarker to determine whether metastatic colorectal cancer patients will benefit from the drug, cetuximab, is whether patients carry a RAS mutation in their tumours. We evaluated additional biomarkers using samples from a Phase III clinical trial led by the Canadian Cancer Trials Group and the Australasian Gastrointestinal Trials Group. Our study identified a germline, heritable biomarker, a FCGR2A polymorphism, that further identifies an additional subgroup of patients who would benefit most from receiving cetuximab. This is important because the drug does have toxicity and is expensive to use; patients who are found not to likely benefit from this drug can go on quickly to try other agents, including participation in clinical trials.

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Advanced colorectal cancer still has a poor prognosis and more active drugs are urgently needed

MedicalResearch.com Interview with:
Silvia Marsoni, M.D.
Director Clinical Research Office
FPO – Istituto di Candiolo IRCCS
Institute for Cancer Research @ Candiolo
10060 Candiolo (TO) – Italy

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Marsoni: In the Lancet Oncology of April 20 2016, clinical investigators of 4 major Italian academic institutions presented the results of the HERACLES trial, the first phase 2 trial in patients with refractory colorectal cancer and HER2 amplification. HERACLES is based on robust preclinical data, previously generated by the same authors in patient-derived xenografts (PDX) of metastatic colorectal cancers harboring amplification of the HER2 oncogene. The HER2 positive PDXs responded to the anti HER2 combination of trastuzumab and lapatinib, but not to either drug alone.

After validation of the commercial assays to test for HER2 positivity in colorectal cancer specimens, the authors tested the experimentally selected combination of trastuzumab plus lapatinib in HER2-amplified metastatic colorectal cancer patients. They screened 914 patients who were refractory to chemotherapy and had KRAS codon 12/13 wild-type colorectal carcinoma, identifying 46 patients as having HER2-positive disease, enrolling 27 eligible patients into the study. Eight (30%) patients achieved objective responses — the highest proportion ever reported in treatment-refractory patients. One (4%) patient achieved a complete response; 20 (74%) achieved eithera complete response, partial response, or stable disease; median response duration was 9·5 months, median progression-free survival was 5·2 months (95% CI 4–8); and median overall survival was 11·5 months (95% CI 8–17). In this heavily pretreated population – all patients had received and failed standard chemotherapies and anti EGFR antibodies, and mostly also anti-agiogenic therapy – , these outcome data are extraordinary, and they show the relevance of HER2 as a target in the treatment of colorectal cancer. These results represent a breakthrough, even though they apply to a limited subgroup of patients of a very common and lethal malignancy.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Marsoni: This is the first trial to assess the combination of trastuzumab and lapatinib in patients with HER2-positive colorectal carcinoma. Our findings show that the dual HER2-targeted therapy of trastuzumab and lapatinib is active, in the absence of any chemotherapy backbone, in heavily pretreated patients with metastatic disease. Additionally, our results indicate that the extent of HER2 gene copy number elevation and HER2 expression might be associated with response to treatment.

Dr. Marsoni: What recommendations do you have for future research as a result of this study?

Dr. Marsoni: The results of this study could change the day-to-day clinical care management of patients with advanced HER2-positive colorectal cancer. Our findings could lead to the use of trastuzumab and lapatinib in earlier lines of treatment, with a possibility of chemotherapy-free regimens, for patients with HER2-positive tumors. A phase 3 trial is warranted to provide more definitive data.

MedicalResearch.com: Is there anything else the authors would like to state?

Silvia Marsoni, the trial clinical coordinator at the Candiolo Cancer Institute in Turin, states that “Our results show that HER2 amplification is a clinically relevant genetic alteration in metastatic colorectal cancer. This alteration can be screened for with established diagnostic tools, can be acted on at the therapeutic level, and occurs in 3–5% of patients with KRAS codon 12/13 wild-type metastatic colorectal cancer, similar to that of other genetic alterations for which licensed drugs are effective (eg, in lung cancer).”

Livio Trusolino, who conducted the preclinical studies at the Candiolo Cancer Institute, states that “Our results have been achieved through a precision oncology programme that started with preclinical findings in pertinent in-vivo models, was strengthened by a rigorous methodological effort for molecular diagnosis, and finally resulted in the identification of a new therapeutic option for patients with HER2-positive colorectal cancer tumours”.

Finally, Salvatore Siena from the Niguarda Cancer Center in Milan, the principal investigator of the clinical programme, states “We are proud to provide positive results of a targeted therapy for metastatic colorectal cancer, several years after the first publication in 2004 of the efficacy of EGFR-targeted monoclonal antibody. HER2-targeted therapy is a new tool in the therapeutic armamentarium for HER2-positive metastatic colorectal cancer”.

HERACLES is an independent research trial funded by the major Italian cancer charity AIRC (Associazione Italiana per la Ricerca sul Cancro – Programma Speciale AIRC 5per1000) and by the Fondazione Oncologia Niguarda. We also acknowledge contributions from F Hoffman-La Roche.

Citation:

Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial

Sartore-Bianchi, Andrea et al. Published Online: 20 April 2016

The Lancet Oncology , Volume 0 , Issue 0 ,
DOI: http://dx.doi.org/10.1016/S1470-2045(16)00150-9

 

Stool Test May Get More People To Be Screened For Colon Cancer

Douglas A. Corley, MD, PhD Gastroenterologist and Research Scientist III Division of Research Kaiser Permanente Oakland, CA

Dr. Douglas Corley

MedicalResearch.com Interview with:
Douglas A. Corley, MD, PhD

Gastroenterologist and Research Scientist III
Division of Research
Kaiser Permanente
Oakland, CA 

Medical Research: What is the background for this study? What are the main findings?

Dr. Corley: Colorectal cancer is a leading cause of cancer death in the United States, so understanding how cancer screening tests for this cancer are used and if they are effective is extremely important.

There are two commonly used tests for colorectal cancer screening in the United States: colonoscopy and fecal immunochemical tests (also known as “FIT”). Colonoscopy requires a bowel preparation to clean you out and is invasive but, if normal, it is done infrequently (every ten years).

FIT is simple to do at home but, to be most effective, needs to be done every year. This has the advantage of potentially picking up cancers that grow between tests. There are few studies that have looked at how well FIT picks up cancers when used year after year. If a test picks up most cancers, it is said to be very “sensitive” for picking up cancer. Most studies only looked at 1 or 2 years of use for how well FITdetected cancers. It is possible that the first year of use may “clear out” most of the easily detectable cancers and that FIT might not work as well in subsequent years.

This very large study over several years at Kaisier Permanente, where we use both colonoscopy and FIT for colorectal cancer screening, looked at whether FIT worked as well at detecting cancer in years 3 and 4 as it did the first time someone used it.

We found that the sensitivity was highest in the first year, likely from clearing out cancers that were there for a while and easily detected, but that in subsequent years the sensitivity, though 5-10% lower, remained high. Also, most people who started with FIT continued doing it, suggesting that it is both feasible and effective for colorectal cancer screening.

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Male Pattern Baldness Linked To Increased Risk of Colon Polyps

Dr. Nana Keum, PhD Department of Nutrition Harvard T.H. Chan School of Public Health Boston, MA

Dr. NaNa Keum

More on Colon Cancer on MedicalResearch.com
MedicalResearch.com Interview with:
Dr. Nana Keum, PhD
Department of Nutrition
Harvard T.H. Chan School of Public Health
Boston, MA

Medical Research: What is the background for this study? What are the main findings?

Dr. Keum: Male pattern baldness, the most common type of hair loss in men, is positively associated with androgens as well as IGF-1 and insulin, all of which are implicated in pathogenesis of colorectal neoplasia.  Therefore, it is biologically plausible that male pattern baldness, as a marker of underlying aberration in the regulation of the aforementioned hormones, may be associated with colorectal neoplasia.  In our study that examined the relationship between five male hair pattern at age 45 years (no-baldness, frontal-only-baldness, frontal-plus-mild-vertex-baldness, frontal-plus-moderate-vertex-baldness, and frontal-plus-severe-vertex-baldness) and the risk of colorectal adenoma and cancer, we found that frontal-only-baldness and frontal-plus-mild-vertex-baldness were associated with approximately 30% increased risk of colon cancer relative to no-baldness.  Frontal-only-baldness was also positively associated with colorectal adenoma.

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Split Bowel Prep For Colonoscopy Results In More Polyps Detected

Dr Franco Radaelli Division of Digestive Endoscopy and Gastroenterology Valduce Hospital Como, Italy

Dr. Franco Radaelli

MedicalResearch.com Interview with:
Dr Franco Radaelli
Division of Digestive Endoscopy and Gastroenterology
Valduce Hospital
Como, Italy 

Medical Research: What is the background for this study?

Dr. Radaelli: Split regimens of bowel preparation are strongly recommended by European and American Guidelines as they have been associated with a higher level of colon cleansing. However, there is still uncertainty on whether the higher level of cleansing associated with a split regimen also results in a higher proportion of subjects with at least one adenoma (adenoma detection rate, ADR), that represents by far a more relevant quality indicator than the level of cleansing itself.

On this background, we designed a randomized investigator-blinded controlled trial to evaluate whether a “split regimen” of low-volume 2-L PEG-ascorbate solution was superior to the traditional “full dose, the day before regimen” in terms of ADR. Differently from other studies on bowel preparation, we considered adenoma detection rate  instead of the level of colon cleansing, the primary study end-point, and we designed the sample size accordingly. A precise estimation of the sample size was facilitated by including an homogeneous population of asymptomatic subjects undergoing first colonoscopy after positive-FIT within CRC organized screening program. Besides, ADR represents a very solid end-point due to the very low inter-pathology variability in the differential diagnosis between neoplastic and non-neoplastic lesions, while the assessment of the level of cleansing is hampered by unavoidable degree of subjectivity and higher degree of inter-operator variability.

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Quality Improvement in Colon Cancer Care Linked to Lower Costs

MedicalResearch.com Interview with: Johannes Govaert MD Department of Surgery Leiden University Medical Center Leiden, The Netherlands Medical Research: What is the background for this study? Dr. Govaert: The Value Based Health Care agenda of prof. Porter (Harvard Business School) suggests that focus in healthcare should shift from reducing costs to improving quality: where quality of healthcare improves, cost reduction will follow. One of the cornerstones of potential cost reduction, as mentioned by Porter, could be availability of key clinical data on processes and outcomes of care. Despite the important societal and economical role the healthcare system fulfils, it still lags behind when it comes to standardised reporting processes. With the introduction of the Dutch Surgical Colorectal Audit (DSCA) in 2009, robust quality information became available enabling monitoring, evaluation and improvement of surgical colorectal cancer care in the Netherlands. Since the introduction of the DSCA postoperative morbidity and mortality declined. Primary aim of this study was to investigate whether improving quality of surgical colorectal cancer care, by using a national quality improvement initiative, leads to a reduction of hospital costs. Detailed clinical data was obtained from the 2010-2012 population-based Dutch Surgical Colorectal Audit. Costs at patient-level were measured uniformly in all 29 participating hospitals and based on Time-Driven Activity-Based Costing. Medical Research: What are the main findings? Dr. Govaert: Over three consecutive years (2010-2012) severe complications and mortality after colorectal cancer surgery respectively declined with 20% and 29%. Simultaneously, costs during primary admission decreased with 9% without increase in costs within the first 90 days after discharge. Moreover, an inverse relationship (at hospital level) between severe complication rate and hospital costs was identified among the 29 participating hospitals. Hospitals with increasing severe complication rates (between 2010 and 2012) were associated with increasing costs whereas hospitals with declining severe complication rates were associated with cost reduction. Medical Research: What should clinicians and patients take away from your report? Dr. Govaert: This report presents evidence for simultaneously quality improvement and cost reduction. By participation in a nationwide quality improvement initiative with continuous quality measurement and benchmarked feedback, opportunities for targeted improvements are revealed and therefore bringing the medical field forward in improving value of healthcare delivery. Medical Research: What recommendations do you have for future research as a result of this study? Dr. Govaert: This is the first study outside the United States to describe such inverse relationship based on original financial and clinical data. Our conclusions provide additional evidence for cost reduction by quality improvement programs as seen in the American College of Surgeons National Surgical Quality Improvement Program. Therefore, we believe that our findings should be impetus for healthcare providers to focus on improving quality, which will catalyze costs savings as well. Citation: Nationwide Outcome-Measurement in Colorectal Cancer Surgery: Improving Quality and Reducing Costs Govaert, Johannes A. et al. Journal of the American College of Surgeons DOI: http://dx.doi.org/10.1016/j.jamcollsurg.2015.09.020

Dr. Grovaert

MedicalResearch.com Interview with:
Johannes Govaert MD
Department of Surgery
Leiden University Medical Center
Leiden, The Netherlands

Medical Research: What is the background for this study?

Dr. Govaert: The Value Based Health Care agenda ofPprof. Porter (Harvard Business School) suggests that focus in healthcare should shift from reducing costs to improving quality: where quality of healthcare improves, cost reduction will follow. One of the cornerstones of potential cost reduction, as mentioned by Porter, could be availability of key clinical data on processes and outcomes of care. Despite the important societal and economical role the healthcare system fulfils, it still lags behind when it comes to standardised reporting processes. With the introduction of the Dutch Surgical Colorectal Audit (DSCA) in 2009, robust quality information became available enabling monitoring, evaluation and improvement of surgical colorectal cancer care in the Netherlands. Since the introduction of the DSCA postoperative morbidity and mortality declined.

Primary aim of this study was to investigate whether improving quality of surgical colorectal cancer care, by using a national quality improvement initiative, leads to a reduction of hospital costs. Detailed clinical data was obtained from the 2010-2012 population-based Dutch Surgical Colorectal Audit. Costs at patient-level were measured uniformly in all 29 participating hospitals and based on Time-Driven Activity-Based Costing.

Medical Research: What are the main findings?

Dr. Govaert: Over three consecutive years (2010-2012) severe complications and mortality after colorectal cancer surgery respectively declined with 20% and 29%. Simultaneously, costs during primary admission decreased with 9% without increase in costs within the first 90 days after discharge. Moreover, an inverse relationship (at hospital level) between severe complication rate and hospital costs was identified among the 29 participating hospitals. Hospitals with increasing severe complication rates (between 2010 and 2012) were associated with increasing costs whereas hospitals with declining severe complication rates were associated with cost reduction.

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Preventable Colon Cancer Deaths Take Large Fiscal Toll In Poor Communities

Hannah K. Weir, PhD, MSc Senior Epidemiologist CDC

Dr. Weir

MedicalResearch.com Interview with:
Hannah K. Weir, PhD, MSc
Senior Epidemiologist
CDC

Medical Research: What is the background for this study? What are the main findings?

Dr. Weir: Colorectal cancer (CRC) is one of the leading causes of cancer related deaths in the United States.

We know that the risk of dying from colorectal cancer  is not the same across all communities – people living in poorer communities have a higher risk of dying from colorectal cancer than people living in wealthier, better educated communities.

In this study, we estimated the number of potentially avoidable CRC deaths between 2008 and 2012 in poorer communities.  Then we estimated the value of lost productivity that resulted from these deaths. Lost productivity includes the value of future lost salaries, wages, and the value to household activities such as cooking, cleaning, and child care.

We focused on the age group 50 to 74 years because this is the age group where routine CRC screening is recommended. We estimated that more than 14,000 CRC deaths in poorer communities could have been avoided and that these CRC deaths resulted in a nearly $6.5 billion dollars loss in productivity.

This is tragic – for the person who died, their family and for their community. This loss in productivity contributes to the economic burden of these already disadvantaged communities.

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Plasma cfDNA Can Monitor Response To Metastatic Colon Cancer Treatment

Van K. Morris, M.D. Assistant Professor, GI Medical Oncology University of Texas – M.D. Anderson Cancer Center Houston, TX 77030

Dr. Morris

MedicalResearch.com Interview with:
Van K. Morris,  M.D.
Assistant Professor, GI Medical Oncology
University of Texas – M.D. Anderson Cancer Center
Houston, TX 77030 

Medical Research: What is the background for this study? What are the main findings?

Dr. Van K Morris: BRAF V600E mutations are associated with poor clinical outcomes for patients with metastatic colorectal cancer.  Patients were enrolled in a phase I clinical trial with the BRAF inhibitor vemurafenib, the anti-EGFR antibody cetuximab, and irinotecan.  Blood  samples were collected every two weeks with each dose, and plasma was analyzed for changes in the fraction of mutant BRAF V600E allele relative to wild-type BRAF allele with time.  Trends in circulating free DNA (cfDNA) changes were compared with radiographic changes by RECIST 1.1 criteria to examine this technique as a marker for response to therapy.

For patients who had a response radiographically, drastic reductions in the BRAF V600E allele fraction were observed even after two weeks of starting therapy, well before the first restaging scan.  Patients who did not have responses radiographically had less  dramatic changes relative to baseline in the BRAF V600E allele fraction.  This technique analyzing cfDNA from plasma was validated using two different approaches – digital droplet PCR and next-generation sequencing by Guardant Health.  Sequencing of cfDNA was also compared in pretreatment and post-progression samples, and novel mutations in MEK1 and GNAS were observed uniquely in post-progression samples.

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Safety Net Hospital Improves Colon Cancer Screening in Primary Care Setting

Elizabeth Broussard, MD Clinical Assistant Professor Division of Gastroenterology Harborview Medical Center Seattle, WA 98105MedicalResearch.com Interview with:
Elizabeth Broussard, MD
Clinical Assistant Professor
Division of Gastroenterology
Harborview Medical Center
Seattle, WA 98105

Medical Research: What is the background for this study? What are the main findings?

Dr. Broussard: I am a clinical assistant professor of gastroenterology and I practice and teach fellows and residents GI at a safety-net hospital in Seattle and I was seeing too many late stage colorectal cancer (CRC) in our patient population. CRC is preventable with screening, and I wanted to see how the primary care clinics were performing in getting patients screened. When I looked at the baseline percentages, I realized this was an opportunity for improvement. I teamed up with an internal medicine resident Kara Walter, and we did a deep dive into the process of screening. The results of the poster presentation are a product of this teamwork, with cooperation and input from the directors of the six primary care clinics at our hospital. The main findings are that performing the FIT test is complicated and tricky for some patients, that this process can be streamlined with providing a toilet hat, a prepaid postage envelope, and improved and visual instructions. After one year, we saw statistically significant increases in overall screening with FIT in our patient population.

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Young Black Colon Cancer Patients Have Greater Risk of Recurrence

Harry H. Yoon, MD Mayo Clinic Rochester, MN 55905MedicalResearch.com Interview with:
Harry H. Yoon, MD
Mayo Clinic
Rochester, MN 55905

Medical Research: What is the background for this study? What are the main findings?

Dr. Yoon: In the U.S., the survival of patients with colon cancer is known to differ by race, with individuals of black race having worse outcomes than those of white race.

However, it has been difficult to tease apart why the differences in survival exist.

It is generally believed that social or other non-biologic factors (eg, decreased access to care, suboptimal treatment) contribute to the discrepancy.  It’s also known that differences in the general medical condition of patients could affect how long a patient lives.

However, it is unknown whether there are race-based differences in the biology of colon tumors themselves.  This biology can be reflected in the genetic composition of tumors, as well as by whether and how quickly the cancer returns after the patient has undergone surgery and chemotherapy.

In addition, it is unknown whether race-based differences in biology may be related to the age of the patient at the time of diagnosis.  Blacks with colorectal cancer typically have an earlier age of onset than whites do.

A major barrier to addressing these questions are that there are very few large populations of colon cancer patients where everyone had the same disease stage and received uniform treatment, and where patients were monitored for years afterward specifically to see whether the cancer returned.  It is much harder to measure whether cancer has returned (ie, cancer recurrence), as compared to simply knowing whether a patient is alive or dead.  This difference is important, because knowing about cancer recurrence sheds more light on cancer biology than only knowing about patient survival, since many factors unrelated to cancer biology (eg., heart disease) can affect whether a person is alive or dead.

The most reliable data on cancer recurrence (not just patient survival) generally comes from patients who have enrolled in a clinical trial.  In the Alliance N0147 trial, all patients had the same cancer stage (ie, stage III), underwent surgery and received standard of care chemotherapy (ie, “FOLFOX”) after surgery.  Patients had uniform, periodic monitoring after chemotherapy to see if the cancer returned.

In other words, examining racial outcomes in this cohort largely eliminates some of the key factors (eg, decreased access to care, suboptimal treatment) that are believed to contribute to racial discrepancies, and provides a unique opportunity to determine if differences in cancer biology between races may exist.

This study was done to see if colon cancers are genetically different based on race, and whether race-based differences exist in cancer recurrence rates.

The study found that tumors from whites, blacks, and Asians were different in terms of the frequency of mutations in two key cancer-related genes, BRAF and KRAS.  Tumors from whites were twice as likely to have mutated BRAF (14% in whites compared to 6% in Asians and 6% in blacks).  Tumors from blacks had the highest frequency of KRAS mutations (44% in blacks compared to 28% in Asians and 35% in whites).  Tumors from Asians were the mostly likely to have normal copies of both genes (67% in Asians compared to 50% in blacks and 51% in whites).

Next, the study found that the colon cancers among blacks had more than double the risk of cancer recurrence, compared to whites.  However, this discrepancy was only evident among young patients (ie, aged less than 50 years).  Almost 50% of younger black patients experienced colon cancer recurrence within 5 years, compared to ~30% of black patients over age 50, or compared to white or Asian patients regardless of age. The worse outcome among young blacks remained evident even after adjusting for many potential confounding factors, such as tumor grade, the number of malignant nodes, or the presence of BRAF or KRASmutations.  Because this question was examined in a clinical trial cohort of uniform stage and treatment, the role of multiple important potential confounders was diminished.

To our knowledge, this is the first report indicating that colon cancers from young black individuals have a higher chance of relapsing after surgery and chemotherapy, compared to those from white individuals.

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