How can we identify stage III colon cancer patients who do NOT benefit from oxaliplatin-based...

How can we identify stage III colon cancer patients who do NOT benefit from oxaliplatin-based adjuvant therapy?

• Clinical factors alone can best select those NOT likely to benefit– Old School = Wise

• Biomarkers/GEP are better at selecting those NOT likely to benefit– New fangled, latest fad = youthful enthusiasm

Why is this still a question?

• We have relatively few studies• Even in the best studies, adding oxali “fails” 95%

of the time• Oxaliplatin neuropathy does not really go away

as first believed• We have become more responsible, more

balanced with our treatments• Future metrics will be based on outcomes, not

consumption

The Perfect Sorting Hat

Cured by Surgery

Not cured by surgery but 5FU will cure you

Not cured by surgery and chemo will not cure you

Not cured by surgery but 5FU and Oxali will cure you

Testing Today

• KRAS (codon 12, 13)– Generally reserved for met CRC– BRAF sometimes done if KRAS WT

• MSI/MSS– IHC for MLH1, MSH2, MSH6 and PMS2 proteins

• If MLH1 and PMS2 are absent, the patient likely has acquired methylation of the MLH1

• If MSH2 and MSH6 are absent, the patient likely has LS.• If only MSH6 or PMS2 is absent, the patient may have LS.• Up to 15% are still missed, family history still critical

– PCR for MSI-H

NCI: “The prognosis of patients with colon cancer is clearly related to the following:”

• The degree of penetration of the tumor through the bowel wall.

• The presence or absence of nodal involvement.• The presence or absence of distant metastases.Other prognostic factors include the following:• Bowel obstruction and bowel perforation are indicators

of poor prognosis.[7]• Elevated pretreatment serum levels of carcinoembryonic

antigen (CEA) have a negative prognostic significance.[8]

But we need predictive markers

NCCN- Stage 3

• Capecitabine = IV 5FU• Oxaliplatin for all except the elderly (>70)• Rectal ≠ Colon• 6 months

Oncotype DX in C07: J Clin Oncol 30, 2012 (suppl; abstr 3512)

Michael O'Connell et al

• Cox model 5 yr recurrence risk (95%CI) in FU treated pts by RS group (low, int, high): – st II 9% (6-13%), 13% (8-17%), 18% (12-25%); – st IIIA/B 21% (16-26%), 29% (24-34%), 38% (30-46%); – st IIIC 40% (32-48%), 51% (43-59%), 64% (55-74%).

• RS did not have significant interaction w/ stage (p=0.90) or age (p=0.76).

• Relative benefit of Ox was similar across range of RS (interaction p=0.48);

• In Stage III A/B patients, the Recurrence Score result informs whether the absolute benefit of oxalipatin out weighs the risk of toxicities including, the potential for long term neuropathy

No Rx5FU5FU + Oxali

What is the target cell in Adjuvant CRC

• Primary• Micro mets

• Are they the same?

Right Target, Wrong Setting?Epithelial-Mesenchymal Transition (EMT)

Adapted from Kalluri & Weinberg, J Clin Invest 119: 1420-8, 2009

EGFR SyndecanE-cadherin MUC1Cytokeratin DesmoplakinZO-1 a1 (IV) collagenLaminin-1 miR200 familyEntactin

FTS binding protein FAP SnailFSP-1 SlugN-cadherin SIP1Vimentin a-SMAFibronectin Twistb-catenin GoosecoidOb-cadherin LEF-1Syndecan-1 FOXC2miR10b miR21

Inconvenient Truth

Oxaliplatin adds little to overall survival

Kaplan-Meier estimates of overall survival (A) by treatment arm and (B) by treatment arm and by stage (intent-to-treat population).

André T et al. JCO 2009;27:3109-3116

©2009 by American Society of Clinical Oncology

Mosaic trial

Is there a molecular test that can tell me who these 5% are?

Molecular- Schmecular

• The stratification on MOSAIC was based on T stage (T2, 3 versus 4), N stage (0, 1, 2), perforation, obstruction or venous invasion

• NSABP C-07 stratification was based only on N stage (0, 1, 2)

• 80702: Stratification on the number of lymph nodes (1-3; >=4) and aspirin use (no; yes)

Are there other markers?

• MMR• RAF/RAS

• Not that help select treatment

Association of (A) DNA mismatch repair (MMR) status, mutations in (B) BRAFV600E or (C) KRAS, and (D) primary tumor site with disease-free survival in stage III colon carcinomas.

Sinicrope F A et al. JCO 2013;31:3664-3672

©2013 by American Society of Clinical Oncology

Does not predict what chemo to use

Impact of mismatch repair (MMR) status on disease-free survival by primary tumor site.

Sinicrope F A et al. JCO 2013;31:3664-3672

©2013 by American Society of Clinical Oncology

Proximal Distal

Adjusted for T stage, histologic grade, nodal category, age, sex, treatment, tumor site, and mutation status of KRAS and BRAFV600E. dMMR, deficient DNA mismatch repair; HR, hazard ratio; M, multivariate; pMMR, proficient DNA mismatch repair

Impact of (A and B) BRAFV600E or (C and D) KRAS mutations on disease-free survival according to DNA mismatch repair (MMR) status.

Sinicrope F A et al. JCO 2013;31:3664-3672

©2013 by American Society of Clinical Oncology

dMMR + Oxali in Stage III

• Unclear- very little data• Options:

– No treatment– Oxali + 5FU– Non 5FU regimen (ox/iri?)

Old People: Wikipedia

• Old age consists of ages nearing or surpassing the life expectancy of human beings, and thus the end of the human life cycle.

• Old people often have limited regenerative abilities and are more prone to disease, syndromes, and sickness than younger adults.

• The chronological age denoted as “old age” varies culturally and historically. Thus, old age is "a social construct" rather than a definite "biological stage”

Oxali and the elderly

• Old People do not benefit above 5FU– ACCENT database. J Clin Oncol 27(suppl 15):170s,

abstr 4010• Old people do benefit from adding Oxali but

not that much– Sanoff JCO

• Old people do not benefit fro adding oxali– Tournigand, J Clin Oncol. 2012 Sep

20;30(27):3353-60

Percentage of elderly patients with stage III colon cancer treated with chemotherapy. (>75)

Sanoff H K et al. JCO 2012;30:2624-2634

©2012 by American Society of Clinical Oncology

Unadjusted and propensity score–matched Kaplan-Meier survival comparisons of chemotherapy versus no chemotherapy in elderly patients with stage III colon cancer

surviving 120 days from surgery.

Sanoff H K et al. JCO 2012;30:2624-2634

©2012 by American Society of Clinical Oncology

Unadjusted and propensity score–matched Kaplan-Meier survival comparison of oxaliplatin and nonoxaliplatin adjuvant chemotherapy in elderly patients (>75) with stage III colon

cancer.

Sanoff H K et al. JCO 2012;30:2624-2634

©2012 by American Society of Clinical Oncology

SEER unmatched SEER Matched

NYC registry unmatched

NYC registry matched

NCCN unmatched

Rates of (A) disease-free, (B) relapse-free, (C) overall, and (D) post–disease-free survival in patients older than 70 years treated with leucovorin and fluorouracil with oxaliplatin

(FOLFOX4) or without (FL).

Tournigand C et al. JCO 2012;30:3353-3360

©2012 by American Society of Clinical Oncology

Molecular Profiling: Research or Practice

• We believe we need to go this direction• Incredible technology-

– does it reflect the tumor we are treating?• Tumor heterogeneity-

– evolves over time• Proteins, DNA, RNA, miRNA, metabolomics, tumor

chemo-sensitivity assays• Tumor or circulation• Will immune therapy make all of this irrelevant

Sample Reports

Today

• I can order the tests• I get reports• I cannot help but be influenced• Easy: if Rx A > B and both are approved, give A• Assays on the same sample have conflicted• Mutations are different in different contexts

– BRAF melanoma and colon cancer

Tomorrow

• Molecular profiling predicts the right treatment– Outcomes improve

• Regulatory systems in place to support approvals– Revised definitions replacing “Safety and Efficacy”

with “Value”• Payers pay for these new “indications”

– Costs fall, significantly less trial and error

Where we go from here?

Contrast of Appearance vs.Expression Phenotyping

Microarray Low Risk High Risk

Microscope Low Grade High GradeTreatment

Advice

30

Cancer is driven by hyperactive or defective protein circuits

The components of these circuits contain the drug targets of the future.

Patient A Patient B

Each patient’s cancer is different. A drug that works for one patient may not work for another patient with the same cancer.

32

Testing Tomorrow

· “Pan” RAS/RAF testing

· Molecular profiling

Clinical Research 2.0

GI Cancer Patients

Smart Centers

Profile All

Treatment Outcomes

Unified CRF/EMR

BioBank Team

Central Imaging

Central Consent

Data Cloud: Shared & IP Protected

Managed by DSM, STATS

HIPPA compliant,

Regulatory Review

Cancer Centers

Profilers

Pharma + Guidelines

Summary

• We do not have the perfect sorting hat• The current profiling tools are of little help• Traditional risk factors remain our best

determinants for selecting oxaliplatin• Old people should not routinely be offered

oxaliplatin