Continuing my series of posts about the 2013 annual meeting of the American Association for Cancer Research (AACR), I am delighted to publish today a guest post from Philippe Aftimos, MD (@aftimosp) a medical oncologist at the Institut Jules Bordet in Brussels.

Blog readers may recall that Philippe wrote a guest post last year from AACR 2012 in Chicago. Since then he has been promoted from clinical research fellow to the position of medical oncologist and clinical research physician specializing mainly in early clinical trials (phase 1 and 2), new drug development and breast cancer. Congratulations!

It is impossible at large medical and scientific meetings to cover all sessions of interest, so while I followed the theme of resistance, Philippe focused on biomarkers and clinical trial design. I hope you will enjoy reading his reflections on AACR 2013.

Philippe Aftimos, MD writes:

Reflections of a Medical Oncologist on AACR 2013

Washington DC Cherry Blossoms on display for AACR 2013 Picture: Philippe Aftimos

I attended the American Association for Cancer Research Annual Meeting held this year at the Walter E. Washington Convention Center in Washington, DC, April 6 to 10th 2013. I was happy once again by @MaverickNY ‘s invitation to write a guest blog post once the effects of jet lag subsided.

18,000 participants (researchers, scientists, hematologists, medical oncologists, biotech specialist, bio-informaticians,…) conveyed everyday to the convention center and we were all blessed by a beautiful weather and the Cherry Blossoms that bloomed late this year.

Dozens of sessions ran in parallel and the word on every mouth was “sequencing”.  I was instinctively attracted as a clinician to the sessions tackling new drug development, novel biomarker discovery and future clinical trials design. It was clear that the scientific committees did a great job in tailoring a program that could please all of the different participants in the fight against cancer. This was mainly illustrated by the plenary session “From Discovery Science to Precision Medicine: Paving the Path to Progress”:

  • First, a subject with many clinical aspects: “Immune checkpoint blockade: Unleashing the immune system against cancer” presented by Suzanne Topalian. Targeting PD-1 and PD-L1 was also featured in last year’s plenary session.
  • The second subject was translational: “The therapeutic implications of genome sequencing and expression analyses for breast cancer” presented by Charles Perou.
  • The last subject came straight from the bench: “Wnt signaling, Lgr5 stem cells, and cancer” presented by Hans Clevers.

The subject I would like most to discuss is novel biomarker discovery.

Novel Biomarker Discovery

Treatments that do not work are responsible for “wasted” toxicity: wasted resources and, most importantly, “free “ side effects and wasted quality of life to patients. The advent and future “democratic” prices of next generation sequencing and high-throughput technology should help pave the way to “Precision Medicine”, the term that is set to replace “personalized medicine” [1].

Predictive biomarkers of response and/or resistance to anti-cancer therapies are explored at all levels: genome, “transcriptome”, “signalome”, proteins and even imaging. The way to achieve this goal is focusing on individual patients, consecutive sampling, real time science and implementation in therapy.

This is a non-extensive list of what was presented of AACR 2013:

  • PD-L1: the Programmed Death-1 Ligand 1 was presented as a predictive marker of response to anti-PD1 and anti-PD-L1 antibodies at the AACR 2012 plenary session. At the AACR 2013 plenary session, this IHC biomarker was presented as a good prognosis marker, mainly in melanoma and Merkel cell carcinoma.
  • RET fusions and response to cabozantinib (Cometriq, BMS-907351, XL184) in NSCLC: RET fusions are present in 1-2% of cases of Lung adenocarcinoma. 2 of the first 3 patients treated with the RET inhibitor cabozantinib achieved partial response and the third patient had stable disease [2].
  • BRAF(L597) and response to MEK inhibitors in metastatic melanoma: BRAF(L597R) is a somatic mutation in exon 15. A patient with BRAF(L597S) mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Subsequently, study shows that cells harboring BRAF(L597R) mutants are sensitive to MEK inhibitors [3].
  • MAPK1 mutation and sensitivity to erlotinib: a head and neck cancer patient with bi-allelic missense mutation of MAPK1(E322K) presented a complete pathological response after a brief treatment with the anti-EGFR TKI erlotinib. Complete response is still persisting without any adjuvant treatment 1 year later [4].
  • TGF-ß and response to bevacizumab: RNA-seq was performed on core biopsies of 50 breast tumors exposed to bevacizumab in the neo-adjuvant setting. A TGF-ß gene signature was linked to response to bevacizumab. Finally a predictive biomarker to bevacizumab? [5]
  • P-S6 level and response to RAF or MEK inhibitors in melanoma: decreases in ribosomal protein S6 phosphorylation measures TORC1 activity suppression in sensitive melanoma cells. This information can be gathered by sequential and minimally invasive biospies before and early after start of treatment [6].
  • Dynamic BH3 profiling and apoptosis: this concept was difficult for me to understand and I am still not sure that I did understand all the subtlety of the technique. BH3 profiling is a tool designed to measure mitochondrial ‘priming for death’, essentially the proximity of a cell to the threshold of apoptosis. BH3 profiling on cell lines from multiple tumors performed following 16 hours of drug exposure was predictive of cell death. The authors believe in the ability of this technique to identify niche populations sensitive to an individual agent [7].
  • HER-2 mRNA expression and PICK3CA and response to T-DM1: Jose Baselga presented the lessons learned from the EMILIA trial in metastatic HER-2 positive breast cancer (phase 3 trial: T-DM1 vs capecitabine + lapatinib). The tested biomarkers included EGFR, HER-2 and HER-3 mRNA, PIK3CA mutations and PTEN loss. HER-2 mRNA level was correlated with PFS in both treatment arms. PIK3CA mutations were linked to lower efficacy with capecitabine + lapatinib. There was no treatment effect with T-DM1.
  • Predictors of response to BYL719, a PI3Kalpha-specific inhibitor: massive parallel sequencing covering either a panel of 182 cancer-related genes at Foundation Medicine or the whole exome at the Broad Institute of DNA obtained from pre-treatment specimens helped find markers of “insensitivity” to BYL719. Alterations in TP53 and KRAS were identified as statistically significant negative predictors of BYL719 sensitivity while mutations in the APC and PTEN genes were associated with a trend towards lack of benefit from treatment with BYL719 [8].

These markers will still need prospective validation. However, designing trials to achieve that goal will be very challenging. Most of these aberrations are very rare: the MAPK1 (E322k) mutation conferring sensitivity to erlotinib is found in only 1.4% of head and neck cancer patients. Collaborations should be built between institutions and patient referrals cannot remain a taboo. New trial designs such as “umbrella” trials and “basket trials” should be adopted.

Molecular screening programs are being developed in many institutions and smaller trials will eventually be initiated. Smaller trials mean more accurate conclusions, the ability to answer multiple questions and, sometimes, better care for patients.

It is also important to look at previous failures in order to identify the causes. Some of these failures will be explained by our inability to identify predictors of response and resistance. Indeed, very few tumor responses were recorded in a trial testing everolimus in metastatic bladder cancer. Whole-genome sequencing of the tumor of an exceptional responder helped identify TSC1 mutations as a basis for everolimus sensitivity [9].

The US National Cancer Institute (NCI) in Bethesda, Maryland, is launching an “exceptional responders” program [10] to help understand why a few patients benefit from particular treatments that failed the large majority of patients. This program represents, in many researchers’ opinions, a huge step towards “Precision Medicine”.

References:

1-    Momentum grows to make ‘personalized’ medicine more ‘precise’ http://www.nature.com/nm/journal/v19/n3/full/nm0313-249.html

2-    Response to Cabozantinib in Patients with RET Fusion-Positive Lung Adenocarcinomas. Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens PJ, Ross J, Miller VA, Ginsberg MS, Zakowski MF, Kris MG, Ladanyi M, Rizvi NA. Cancer Discov. 2013 Mar 26.

3-    Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, Atefi M, Su Z, Branch S, Lyle PL, Hicks DJ, Bozon V, Glaspy JA, Rosen N, Solit DB, Netterville JL, Vnencak-Jones CL, Sosman JA, Ribas A, Zhao Z, Pao W. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov. 2012 Sep;2(9):791-7.

4-    Lui V, Allen E, Li H, Zhang F, Zeng Y, Johnson J, Garraway L, Mills G, Grandis J. Whole exome sequencing links MAPK1 mutation to exquisite sensitivity to brief erlotinib monotherapy in head and neck cancer [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 4565.

5-    Varadan V, Miskimen K, Kamalakaran S, Janevski A, Banerjee N, Williams N, Abu-Khalaf M, Sikov W, Dimitrova N, Harris L. RNA-seq identifies a TGF-β signature that predicts response to preoperative bevacizumab in breast cancer [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 4566.

6-    Corcoran R, Rothenberg S, Hata A, Faber A, Winokur D, Piris A, Nazarian R, Brown R, Godfrey J, Mino-Kenudson M, Settleman J, Wargo J, Flaherty K, Haber D, Engelman J. Rapid assessment of TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF mutant melanoma [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 4568.

7-    Montero J, Letai A. Personalizing cancer therapy using dynamic BH3 profiling [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 4569.

8-    Rodon J, Juric D, Gonzalez-Angulo A, Bendell J, Berlin J, Bootle D, Gravelin K, Huang A, Derti A, Lehar J, W�rthner J, Boehm M, van Allen E, Wagle N, Garraway L, Yelensky R, Stephens P, Miller V, Schlegel R, Quadt C, Baselga J. Towards defining the genetic framework for clinical response to treatment with BYL719, a PI3Kalpha-specific inhibitor [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 2278.

9-    Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012 Oct 12;338(6104):221

10-Cancer researchers revisit ‘failed’ clinical trials http://www.nature.com/news/cancer-researchers-revisit-failed-clinical-trials-1.12835