“Colon Cancer Update” Christie J. Hilton, DO · “Colon Cancer Update” Christie J. Hilton, DO POMA District VIII 31stAnnual Educational Winter Seminar January 25‐28, 2018

“Colon Cancer Update”Christie J. Hilton, DO

POMA District VIII 31st Annual Educational Winter SeminarJanuary 25‐28, 2018 1

POMA Winter ConferenceChristie Hilton DOMedical Oncology

January 2018

None

Colon Cancer Numbers

Screening (brief update)

Practice changing updates in colon cancer

MSI Testing

Immunotherapy in Colon Cancer



SEER.cancer.gov



SEER.cancer.gov

NCI Surveillance, Epidemiology and End Results Program



SEER.cancer.gov


Colon cancer prevention starts with screening



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.orgColorectal 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

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.




NCCRT.org

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

Not all polyps are the same

NCCN.org Colorectal cancer screening guidelines version 2.2017

Hyperplastic Polyps 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

Not all polyps are the same




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-screening2JAMA. 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

Personal history of

Adenoma

SSP

Colorectal

Cancer

Inflammatory

Bowel Disease

Positive family

history of CRC

RISK GROUPS

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 SyndromeNCCN Colorectal Cancer Screening



Family history without a confirmed genetic syndrome



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




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


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





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



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

Quality of life

PatientPreference

Toxicity profile

Tumor burden Resectability

Tumor location

Tumor Characteristics

Patientcharacteristics

Age

ComorbiditiesPrior adjuvant

treatment

Performance status

Therapy tailored according to individual patient needs

Molecular characteristics

RAS BRAF

MSI-high HER2

Quality of life

PatientPreference

Toxicity profile


Tumor location



Age


treatment

Performance status



RAS BRAF

MSI-high HER2



“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



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

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.

Figure Legend:

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

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.

Figure Legend:

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, 1704–1713NCCN.org



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 dMMRcases.

Deficiency of MMR results in production of a truncated, nonfunctional protein or loss of a protein that causes MSI.

• 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

MSI: microsatellite instability



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 afavorable outcome

• Favorable outcome in Stage III disease limited and mayvary with tumor location

Klingbiel D, PETACC-3 trial. Ann Oncol 2015Sinicrope FA, J Clin Oncol 2013

Base pair mismatch

Normal DNA repair

Defective DNA repair (MMR+)

T C T A C

A G C T G

T C G A C

A G C T G

T C T A C

A G C T G A G A T G

T C T A C

Normal

Microsatellite instability

Addition of nucleotide repeats



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



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



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 studyPrimary 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



On July 31st 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



Quality of life

PatientPreference

Toxicity profile


Tumor location



Age


treatment

Performance status



RAS BRAF

MSI-high HER2

Documents

“Colon Cancer Update” Christie J. Hilton, DO · “Colon Cancer Update” Christie J. Hilton, DO POMA District VIII 31stAnnual Educational Winter Seminar January 25‐28, 2018