POMA Winter Conference Christie Hilton DO Medical Oncology January 2018 None Colon Cancer Numbers Screening (brief update) Practice changing updates in colon cancer MSI Testing Immunotherapy in Colon Cancer January 25 28, 2018 1
Colon Cancer Numbers SEER.cancer.gov Colon Cancer Numbers SEER.cancer.gov NCI Surveillance, Epidemiology and End Results Program January 25 28, 2018 2
Colon Cancer Numbers SEER.cancer.gov Colon cancer prevention starts with screening January 25 28, 2018 3
Screening can reduce colorectal cancer mortality by detecting cancer At a curable stage Potentially decrease CRC incidence by detecting and removing polyps Earlier diagnosis can have an impact on survival NCCN.org Colorectal cancer screening guidelines version 2.2017 Screening can reduce colorectal cancer mortality by detecting cancer At a curable stage Potentially decrease CRC incidence by detecting and removing polyps Earlier diagnosis can have an impact on survival SEER database NCCN.org Colorectal cancer screening guidelines version 2.2017 Impact of screening (at least in part due to screening): Decreased incidence of colon and rectal cancers Mortality from CRC decreased by almost 51% from 1990 to 2014 According to the Centers for Disease Control and Prevention The screening rate among U.S. adults aged 50 to 75 years has increased from approximately 42% in 2000 to 59% in 2010. NCCN.org Colorectal cancer screening guidelines version 2.2017 January 25 28, 2018 4
NCCRT.org Not all polyps are the same Adenoma/Adenomatous Polyps Most common form of polyps Associated with an increased risk for CRC Villous adenomatous polyps have a greater risk of harboring cancer and finding additional adenomatous polyps or cancer on follow-up. Flat adenomatous polyps risk is not defined - prospective studies are required to clarify their role in CRC risk Sessile Serrated Polyps Associated with adenocarcinoma. When they have foci of dysplasia they are termed SSP with cytologic dysplasia (SSP-cd). SSP-cds are thought to be the immediate precursors of MSI sporadic CRC, and any dysplasia in an SSP is thought to be comparable to or more concerning than high grade dysplasia in a conventional adenoma NCCN.org Colorectal cancer screening guidelines version 2.2017 Hyperplastic Polyps Not all polyps are the same In general: they are not associated with a significantly increased risk for CRC Often found in the sigmoid colon and rectum Hyperplastic polyps that are <1 cm without SSP features indicate average risk for follow-up screening when they occur in the rectum and sigmoid colon. Inflammatory polyps /Psuedopolyps Irregular areas of intact colon mucosa which appear after a flare of an inflammatory bowel disease NCCN.org Colorectal cancer screening guidelines version 2.2017 January 25 28, 2018 5
U.S. Preventive Services Task Force final recommendation statement on screening for colorectal cancer recommends screening for colorectal cancer: starting at age 50 years and continuing until age 75 years The decision to screen for colorectal cancer in adults aged 76 to 85 years should be an individual one, taking into account the patient s overall health and prior screening history http://www.uspreventiveservicestaskforce.org/page/document/updatesummaryfinal/colorectal-cancer-screening2 JAMA. 2016;315(23):2576-2594. NCCN also recommends: CRC screening is recommended in adults ages 50 75 y. Because the risk of colorectal screening increases with age, the decision to screen between ages 76 85 y should be individualized and include a discussion of the risks and benefits based on comorbidity status and estimated life expectancy. Individuals who have not been previously screened are most likely to benefit in this age group. NCCN Colorectal Cancer Screening Average Risk Age >/= 50 No History of: Adenoma Sessile serrated polyp (SSP) colorectal cancer Inflammatory bowel disease Negative family history of CRC Increased Risk RISK GROUPS Personal history of Adenoma SSP Colorectal Cancer Inflammatory Bowel Disease Positive family history of CRC high risk lynch syndrome polyposis syndromes familial adenomatous polyposis MUTYH-associated polyposis Peutz-jeghers syndrome Juvenile polyposis syndrome Serrated polyposis syndrome Colonic adenomatous polyposis of unknown etiology Cowden syndrome / PTEN Li-fraumeni Syndrome NCCN Colorectal Cancer Screening January 25 28, 2018 6
Family history without a confirmed genetic syndrome January 25 28, 2018 7
Colonoscopy Most commonly used (in the US) for average and high-risk populations High-sensitivity guaiac-based Requires 3 stool specimens annually (not via digital rectal examination) Diet Any positive test requires further evaluation FIT / FIT-DNA (cologuard) More sensitive than guaiac-based testing - Detects human globin Diet is not required Single stool annually Flexible sigmoidoscopy May be performed alone or in combination with high-sensitivity FOBT or FIT NCCN.org Colorectal cancer screening guidelines version 2.2017 January 25 28, 2018 8
CT Colonography Accuracy >10-mm lesions can be identified - similar to colonoscopy Lesions 5 9 mm can be identified but less accurately than colonoscopy Lesions <5 mm cannot be identified with acceptable accuracy When to refer for colonoscopy Consider when 1 or 2 lesions that are 6 9 mm are found Recommended if >3 lesions that are 6 9 mm or any lesion 10 mm are seen NCCN.org Colorectal cancer screening guidelines version 2.2017 JAMA. 2016;315(23):2576-2594. Stage 0 carcinoma in situ of the colon. Noninvasive. The cancer has not grown beyond the first layer of the colon wall Treatment = endoscopic polypectomy Stage I The cancer has grown into either the second or third layer of the colon wall. Treatment = Resection Stage II The cancer has grown into the fourth layer of or outside the colon wall. Stage III The cancer has spread from the colon to nearby lymph nodes or there are tumor deposits. Tumor deposits are small secondary tumors within the colon. Stage IV The colon cancer has spread to distant organs. Cancer.gov January 25 28, 2018 9
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The current management of disseminated metastatic colon cancer involves various active drugs, either in combination or as single agents: 5-FU/LV Capecitabine Irinotecan Oxaliplatin Bevacizumab Cetuximab Panitumumab Ziv-aflibercept Ramucirumab Regorafenib Pembrolizumab and nivolumab January 25 28, 2018 11
Choice of therapy is based on consideration of : Goals of therapy Type and timing of prior therapy Mutational profile of the tumor Differing toxicity profiles of the drugs Comorbid conditions Patient characteristics Molecular characteristics Comorbidities Prior adjuvant treatment RAS BRAF MSI-high HER2 Age Performance status Tumor Characteristics Patient Preference Tumor burden Resectability Quality of life Toxicity profile Tumor location Therapy tailored according to individual patient needs Patient characteristics Molecular characteristics Comorbidities Age Prior adjuvant treatment Performance status RAS MSI-high BRAF HER2 Tumor Characteristics Patient Preference Tumor burden Resectability Quality of life Toxicity profile Tumor location Therapy tailored according to individual patient needs January 25 28, 2018 12
Metastatic colorectal cancer is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct. OBJECTIVE : To examine the prognostic and predictive value of primary tumor location in patients with RAS wild-type (wt) mcrc treated with first-line FOLFIRI plus cetuximab in the CRYSTAL trial and FOLFIRI Plus Cetuximab VersusFOLFIRI Plus Bevacizumab in the FIRE-3 trial. Retrospective analysis Included patients with RAS wild type metastatic colorectal cancer (eligible for cetuximab) from the CRYSTAL and FIRE-3 trials were classified as having left-sided or right-sided MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS) Overall survival (OS) Objective response rate (ORR) RESULTS RAS wt Patients with left-sided tumors (n = 142 and n = 157, respectively) had Markedly superior PFS, OS, and ORR compared with patients with right-sided tumors (n = 33 and n = 38, respectively). significantly improved: OS relative to the respective comparators (FOLFIRI and FOLFIRI plus bevacizumab); in contrast, in RAS wt patients with right-sided tumors: Limited benefits with the addition of cetuximab to FOLFIRI in CRYSTAL Comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3. CONCLUSIONS AND RELEVANCE In the RAS wt populations of CRYSTAL and FIRE-3, patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors. First-line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors whereas patients with right-sided tumors derived limited benefit from standard treatments January 25 28, 2018 13
From: Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal CancerRetrospective Analyses of the CRYSTAL and FIRE-3 Trials JAMA Oncol. 2017;3(2):194-201. doi:10.1001/jamaoncol.2016.3797 Figure Legend: Survival Characteristics of CRYSTAL Study PatientsA, Progression-free survival (PFS) and (B) overall survival (OS) for RAS wild-type (wt) CRYSTAL study patients, stratified based on tumor location. P values derive from a log-rank test, stratified by region and Eastern Cooperative Oncology Group performance status. FOLFIRI indicates fluorouracil, leucovorin, and irinotecan; HR, hazard ratio; mcrc, metastatic colorectal cancer. From: Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal CancerRetrospective Analyses of the CRYSTAL and FIRE-3 Trials JAMA Oncol. 2017;3(2):194-201. doi:10.1001/jamaoncol.2016.3797 Figure Legend: Survival Characteristics of FIRE-3 Study PatientsA, Progression-free survival (PFS) and (B) overall survival (OS) for RAS wild-type (wt) FIRE-3 study patients, stratified based on tumor location. P values derive from a log-rank test, stratified by region and Eastern Cooperative Oncology Group performance status. FOLFIRI indicates fluorouracil, leucovorin, and irinotecan; HR, hazard ratio; mcrc, metastatic colorectal cancer. KRAS, NRAS Mutation Testing Some treatments for metastatic colon cancer do not work if the RAS genes are mutated RAS mutations are seen in roughly 50% of metastatic CRC Patients with any known KRAS mutation or NRAS mutation should not be treated with either cetuximab or panitumumab BRAF Mutation Testing BRAF V600E mutation makes response to panitumumab or cetuximab unlikely BRAF mutation in found in 5-10% of metastatic CRC Microsatellite Instability (MSI) or Mismatch Repair (MMR) Testing Eur. J. Cancer 2015, 51, 1704 1713 NCCN.org January 25 28, 2018 14
Normal MMR (mismatch repair) proteins correct DNA errors that occur when copies of DNA are being made Defective MMR (mismatch repair) MMR mutations cause one or more MMR proteins to be absent or epigenetic silencing of the genes DNA errors aren t corrected and the number of gene mutations increases DNA errors caused by dmmr often occur in microsatellites Microsatellites are a part of the DNA code that is repeated many times in a row Due to dmmr, microsatellites may be shorter or longer than normal = MSI (microsatellite instability). Loss of MMR proteins and MSI are features of Lynch syndrome. Loss of MMR proteins and MSI can occur in the absence of Lynch syndrome 1 3-15% of colon cancers (percent decreases as stage advances) Br J Cancer.2009 Jan 27;100(2):266-73. NCCN.org DNA MMR system is composed of 4 MMR genes and their encoded proteins (MLH1, MSH2, MSH6, PMS2). Inactivation of MLH1 and MSH2 account for over 90% of dmmr cases. Deficiency of MMR results in production of a truncated, nonfunctional protein or loss of a protein that causes MSI. MSI: microsatellite instability Germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2): LYNCH SYNDROME 2-4% colon cancers Somatic defects: 19% CRC Somatic hypermethylation of MLH1 gene promoter results in inactivation of the gene: 52% colon cancers January 25 28, 2018 15
MSI: microsatellite instability MSI-H more common in Stage II than Stage III ds 22% vs 12% p<.0001 Stage IV tumors that are MSI-H: 3.5% Stage II pts MSI-H is a prognostic marker for a favorable outcome Favorable outcome in Stage III disease limited and may vary with tumor location Klingbiel D, PETACC-3 trial. Ann Oncol 2015 Sinicrope FA, J Clin Oncol 2013 Base pair mismatch T C T A C Normal DNA repair T C G A C A G C T G A G C T G Defective DNA repair (MMR+) T C T A C A G C T G T C T A C A G A T G Normal Microsatellite instability Addition of nucleotide repeats January 25 28, 2018 16
Mutations in MMR (inherited) or loss of MMR by methylation (acquired) results in microsatellite instability (MSI) Increased duplication of tandem dinucleotide repeats (microsatellites) Resulting increased mutation rate and leads to a higher risk of colon cancer Genetic signature of tumors with deficient MMR is a high number of DNA replication errors and high levels of DNA microsatellite instability (MSI). Unique clinicopathologic features are noted in these tumors Lymphocyte infiltrate Crohn s-like reaction Poorly differentiated Right sided lesions January 25 28, 2018 17
In general CRC was thought to be an non-immunogenic tumor type However a subset of CRC was noted to have infiltration of the tumor by specific T cell immune infiltrates which correlated with better disease-free and overall survival at all tumor stages. Based on research in the melanoma is hypothesized that neoantigens generated from tumor specific mutations of self antigens may be recognized by the immune system and therefore triggering anti tumor immune response Tumors that lack the mismatch repair mechanism harbor more mutations than do tumors which are MMR proficient and the errors in DNA replication create neoantigens which have the potential to be recognized as non-self Cancers 2017, 9, 50; doi:10.3390/cancers9050050 January 25 28, 2018 18
METHODS: Multicentre (31 sites in 8 countries) Open-label, phase 2 trial PATIENTS 18 years of age with recurrent or metastatic colorectal cancer locally assessed as dmmr/msi-h Progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. TREATMENT: 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable side effects, or withdrawal from study Primary endpoint was investigator-assessed objective response (RECIST) All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188. Lancet Oncol. 2017 Sep;18(9):1182-1191. FINDINGS: 74 patients 40 patients (54%) had received three or more previous treatments. At a median follow-up of 12months: 23 of 74 patients achieved an investigator-assessed objective response 51 of 74 patients had disease control for 12 weeks or longer Median duration of response was not yet reached All responders were alive 8 patients had responses lasting 12 months or longer The most common grade 3 or 4 drug-related adverse events were: Increased concentrations of lipase (six [8%]) and amylase (two [3%]) 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator. Bottom Line: Nivolumab provided durable responses A loss or deficiency of any of these proteins (MLH1, MSH2, PMS2, MSH6) suggests potential MSI-H status and warrants further testing with PCR to confirm MSI-H. If all 4 proteins are intact or present the tumor is microsatellite stable or MMR proficient and unlikely to respond to checkpoint inhibitor monotherapy January 25 28, 2018 19
On July 31 st the FDA granted accelerated approval of nivolumab in metastatic colorectal cancer that has progressed after chemotherapy and is microsatellite instability high (MSI-H) and deficient in mismatch repair (dmmr). Because tumor cells with these features tend to have more genetic mutations they are more likely to be recognized by the immune system. In the phase II Checkmate clinical trial 28% of patients treated with nivolumab experienced an objective response to treatment: their tumors shrank, as measured by regular imaging scans. One of the trial participants had a complete response. Although fewer than one-third of the 74 participants in the trial responded to treatment - the responses were durable and the patient has had fewer side effects than seen with conventional chemotherapy. Common Grade 1 and 2 side effects included: fatigue rash musculoskeletal pain gastrointestinal side effects. MSI-H/dMMR tumors make up only about 5% of all metastatic colorectal cancers Pembrolizumab (anti-pd-1) For ALL unresectable or metastatic MSI-H or MMR-deficient SOLID TUMORS (pediatric and adult) that have progressed on prior treatment and with no satisfactory alternative treatment options For MSI-H or MMR-deficient CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan Advanced or metastatic PD-L1+ Gastric or GEJ adenocarcinoma after 2 lines of therapy including fluoropyrimidine- and platinum-containing regimens and, HER2- targeted therapy if appropriate Nivolumab (anti-pd-1) For MSI-H or MMR-deficient CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan For hepatocellular carcinoma previously treated with sorafenib January 25 28, 2018 20
Patient characteristics Molecular characteristics Comorbidities Prior adjuvant treatment RAS BRAF MSI-high HER2 Age Performance status Tumor Characteristics Patient Preference Tumor burden Resectability Quality of life Toxicity profile Tumor location Therapy tailored according to individual patient needs January 25 28, 2018 21