2015 ASCO in Review 

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Speaker:Dustin Deming, MD is a gastrointestinal oncologist at the University of Wisconsin Carbone Cancer Center (UWCCC) and the William S Middleton Veterans Hospital. Dr. Deming has a subspecialty focus in the treatment of colon, rectal and anal cancers. His research aims to fundamentally change the way in which we treat gastrointestinal cancers to a more personalized approach. In addition to Dr. Deming’s targeted therapy research in the lab, he has also been active in early phase clinical trials. He has developed the concepts and chaired several NCI/CTEP sponsored phase I clinical trials.

Dr. Deming is also a CRC survivor. At age 31, he was diagnosed with stage III rectal cancer, the very disease he has dedicated to treating and advancing therapies for. As both a practitioner, researcher AND a patient, he knows first-hand what the cancer journey is like.

2015 ASCO Annual Meeting

May 29-June 2, 2015 | Chicago

Dustin Deming, MD University of Wisconsin

About Me

Gastrointestinal Oncologist at the University of Wisconsin Carbone Cancer Center

Clinical and Basic Science Researcher with my own laboratory dedicated to developing new therapies for CRC

Rectal cancer patient – diagnosed 3 years ago with stage III rectal cancer

Why is the ASCO Annual Meeting Important?

The American Society of Clinical Oncology is the nation’s leading clinical oncology society

The ASCO Annual Meeting brings together over 30,000 oncology professionals

Scientific sessions present the latest ground breaking research from around the world

Educational sessions offer expert opinions regarding controversial topics

Networking platform for the development of the next generation of laboratory investigations and clinical trials

Advancements in CRC

Therapies for subtypes of CRC BRAF mutant HER2 Amplified MMR Deficiency/MSI High

Survivorship Care Aspirin Vitamin D

Biology of CRC

The more we learn about CRC the more we are realizing that it is not just one disease, but a collection of many different subtypes that we can distinguish based on the biology of the cancers.

Normal Metastases

HyperplasiaEarly

AdenomaIntermediate

AdenomaLate

Adenoma Carcinoma

APC

BRAFKRASMLH1MSH2

SMAD4TGFBR2

TP53PIK3CA

Stratified By MutationProfile

OptimalTherapy

Biomarkers/MolecularImaging

Or

Colorectal CancerPatient Population

www.biooncology.com/biological-pathways/her-signaling

CRC Subgroups Currently Being Tested for in the Clinic

KRAS, NRAS and BRAF mutations are known to result in resistance to commonly used drugs like cetuximab and panitumumab

If a patient has stage IV cancer, then their cancer should be tested for these mutations and cetuximab and panitumumab should not be given.

This testing is a great advance as these patients who would not have received benefit from these therapies will not be exposed to the risks of these drugs.

BRAF This mutation results in the

development of aggressive cancers and results in a poor survival.

Present in 10% of CRCs

This regimen was tolerated fairly well with fatigue, nausea, diarrhea and rash being the most common side effects.

6/17 (35%) patients had a partial response

A cooperative group trial looking further at this regimen for the BRAF mutant group is currently ongoing.

Phase Ib study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated metastatic colorectal cancer and advanced cancers.

David Hong, et al.

HER2 Amplification

Therapeutic dual inhibition of HER2 Pathway in Metastatic Colorectal Cancer – The Heracles Trial

Salvatore Siena, et al

5.4% of metastatic CRCs have have HER2 amplification

Examined combination of Trastuzumab and Lapatinib

Therapy was well tolerated

34.7% of patients had a partial response

Clinical trials will be analyzing this regimen further

MMR deficiency/MSI-High

Mismatch repair (MMR) deficiency occurs in ~15% of all CRCs, most commonly related mutations in MLH1 or MSH2

MMR deficiency overall has an improved prognosis, but has also been shown to result in decreased responsiveness to 5-fluorouracil

Microsatellite instability is a way of testing that MMR is deficient by detecting abnormalities in certain segments of the DNA

If these MMR genes are mutated then these cancer cells can develop 100s to 1000s of mutations

Due to all of these abnormalities in the cell, it is possible that these cells will look more abnormal to the immune system as compared to other cancer cells that do not have these abnormalities.

In the metastatic setting this groups is about 5% of CRCs

Testing for MSI status or MMR abnormalities is standard at many cancer centers

MSI-High or MMR deficient tumors

PD-1 blockade in tumors with mismatch-repair deficiency.

Le, et al

Examined pembrolizumab (anti-PD1 immunotherapy) treatment in patients with MMR deficient tumors

4/10 (40%) of patients developed a partial response

Therapy is well tolerated

Will be studied further in likely multiple different clinical trials

Why is this important?

There is a lot of hope that we are getting better at treating CRC

This is just the beginning of the improvements that will be seen as personalized medicine becomes a reality for CRC

Multiple clinical trials are underway or in development that will explore treatments for these and other subtypes of CRC

This also comes with many questions and uncertainties

Who should get tested?

What testing should be done?

When should this testing be done?

Which mutations or abnormalities in the cells are most important?

How does this all get paid for?

NCI Match Trial

www.cancer.gov

Survivorship Care:Aspirin

Impact of aspirin as secondary prevention in an unselected cohort of 25,644 patients with colorectal cancer: A population-based study

Simer Bains, et al

Study examined aspirin use or not after a diagnosis of CRC

Most patients has stage II or III CRC

For patients with resected CRC aspirin improves overall survival and colorectal cancer specific survival

Aspirin 81-325 mg is recommended for patients with CRC

Vitamin D

Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405

Kimmie Ng, et al

Patients with metastatic CRC are often have low vitamin D

Low vitamin D was seen in people living in the North or Northeast, in winter/spring months, obese patients, less active patients, and those not taking supplementation.

In this study people with lower vitamin D levels did not live as long as those with higher levels.

Studies are needed to determine if supplementation will improve survival for metastatic CRC patients.

What do I tell my patients and do myself?

What is good for CRC prevention is good for your health in general

Daily aspirin (81-325 mg) Daily exercise (at least 30 min 3 times per week) Low glycemic index diet Possible benefit daily multivitamin

(calcium and vitamin D)

Future Directions

There is a lot of exciting early phase clinical trials for subtypes of CRC. Confirmatory studies for these subtypes are either ongoing or in development.

BRAF

HER2 Amplified

MMR deficient – immunotherapy

NCI MATCH Trial

PIK3CA mutant

Deming Laboratory

CRCs with PIK3CA mutations without KRAS, NRAS or BRAF mutations are sensitive to inhibition of this pathway.

Culture medium

Matrigel Spheroid

Question & Answer:

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