IMPAKT 2013 Press Release: Study Opens New Prospects for Developing Dew Targeted Therapies for Breast Cancer

Lugano-CH, Brussels-BE, 2 May 2013

A study led by prominent breast cancer experts from Europe and the US has revealed a number of potentially important prospects for targeted therapies, and brings opportunities of truly personalised therapy for breast cancer a step closer, researchers said at the 5th IMPAKT Breast Cancer Conference in Brussels, Belgium.

The IMPAKT meeting presents cutting edge, ‘translational’ breast cancer research that is beginning to have an impact for patients.

This current study was led by Dr Martine Piccart, Director of Medicine at the Jules Bordet Institute in Brussels, and Dr Jose Baselga, Associate Director at Memorial Sloan-Kettering Cancer Center, New York.

The researchers used modern sequencing technology to characterise the genetic aberrations of cancer genes present in tumour samples from a well-defined cohort of advanced postmenopausal patients who were enrolled in the BOLERO-2 clinical trial.

“The results of this study generated hypotheses for developing more rational targeted therapy combinations based on the specific genetic aberrations present in each individual tumour,” Dr Piccart said.

“This work, together with previous works published last year, highlights again the genetic heterogeneity of breast cancer. These results show that tumours that may look very similar at the clinical level, can be genetically very different, suggesting that they may require different treatment strategies.”

“There is still a long way to go before we will be able to offer truly personalised therapies to cancer patients, and support for research such as this will be critical to accelerate this process,” Dr Piccart said.

The study involved postmenopausal women with advanced breast cancer that was hormone receptor positive and HER2 negative taking part in the BOLERO-2 phase III trial. The trial showed that everolimus plus exemestane significantly improved progression-free survival, response rate and clinical benefit rate versus placebo plus exemestane. Although benefits were seen in all prospectively defined subgroups of women who took part, the researchers noted some variations, partially due to genetic differences in molecular determinants of everolimus sensitivity and interactions between the oestrogen receptor and mTOR pathways.

In the current analysis, researchers used next-generation sequencing to assess genetic alterations in archival tumour specimens from 230 tumours. They analysed coding regions of 182 cancer-related genes for sequence and copy number variations.

All patients had at least one genetic alteration, and 98% had more than 2, the researchers report. A total of 173 different genes were altered in at least one of the tumour samples. Among the frequently mutated genes were PIK3CA, TP53 and ARID1A.

“Some mutations were found to cluster into similar pathways, for which targeted therapies could potentially be used,” Dr Piccart said.

“Although in many cases we cannot be sure what effect the mutations have on the tumour characteristics or the clinical efficacy of treatments, we did find that mutations in the tumour suppressor gene PTEN were associated with loss of protein expression and function.”

The authors also found an increased mutation rate for the oestrogen receptor, a key player in breast cancer, between primary and metastatic samples, which highlights potentially clinically relevant differences between the primary and metastatic disease for this group of hormone-receptor positive patients.

More generally, the results illustrate that this kind of sequencing is feasible in phase III studies, the researchers say.

“The ability to carry on large-scale sequencing in phase III trials will potentially help us understand why some patients did show a good clinical response to the investigated drugs whereas others did not. Also, being able to sequence cancer genes in well-described clinically homogeneous cohorts of clinical trials will help to build new hypotheses regarding future targeted treatment strategies.”

Dr Fabrice Andre from the Department of Medical Oncology at Institut Gustave Roussy, Villejuif, France, who was not involved in the research, said the study has two major impacts for clinical research.

First, he said, it suggests that next generation sequencing can be applied in the daily practice using archival samples. This opens new avenues for the development of personalised medicine trials. Second, by discovering new genomic segments, this study will certainly lead to the development of new biomarker-driven trials.

“This is a pioneering study in the field of personalised therapy for breast cancer since it shows for the first time that next generation sequencing can be applied to ‘real-life’ samples of patients with breast cancer. Until now, most of the data from next generation sequencing have been obtained with frozen tissue specifically for this purpose,” Dr Andre said.

“Interestingly, this study, done in patients who have relapsed, shows an increased frequency of mutations in important genes like ESR1, IGF1R. This could lead to the development of new trials testing compounds against these genomic segments,” Dr Andre said.

Following this study, prospective trials are needed to test whether the use of genomics could improve outcomes for patients, he said. “Also, we still need a comprehensive analysis of metastatic tissue in order to better develop drugs and understand the metastatic phenomenon. These two purposes will be addressed in the large pan-European effort called PRISM and led by Breast International Group (BIG).”

Notes to Editors

Session info: PI3K/AKT/mTOR: Targets/trials and biomarkers. An horizon scan and debate

Friday, 3 May 2013, 09:00 AM – 10:25 AM (CEST). Place: Gold Hall.

Please contact the IMPAKT Press Office at media@esmo.org to schedule remote interviews or for any inquiry.

About the Breast International Group (BIG)

The Breast International Group (BIG) is a non-profit organisation for academic breast cancer research groups from around the world, based in Brussels, Belgium.

Founded by leading European opinion leaders in 1996, BIG now constitutes a network of 50 groups based in Europe, Canada, Latin America, Asia and Australasia. These research entities are tied to several thousand specialised hospitals and research centres worldwide. More than 30 clinical trials are run or are under development under the BIG umbrella. BIG also works closely with the US National Cancer Institute (NCI) and the North American Breast Cancer Groups (NABCG), so that together they act as a strong integrating force in the breast cancer research arena.

To make significant scientific advances in breast cancer research, reduce unnecessary duplication of effort, and optimally serve those affected by the disease, large-scale cooperation is crucial. Therefore BIG facilitates breast cancer research at international level, by stimulating cooperation between its members and other academic networks, and collaborating with, but working independently from, the pharmaceutical industry. To find out more about BIG, please visit: www.breastinternationalgroup.org

About the European Society for Medical Oncology (ESMO)

The European Society for Medical Oncology (ESMO) is the leading European professional organization committed to advancing the specialty of medical oncology and promoting a multidisciplinary approach to cancer treatment and care.

ESMO’s mission is to advance cancer care and cure through fostering and disseminating good science that leads to better medicine and determines best practice.

As a trusted organization with 35 years of experience, ESMO serves its members and the oncology community through: a brand of excellence in post-graduate oncology education and training; leadership in transforming evidence-based research into standards of cancer care in Europe; dedicated efforts to foster a more favorable environment for scientific research; innovative international platforms to share expertise, best practices and disseminate the most up-to-date scientific research to as wide an audience as possible.

ESMO’s scientific journal,Annals of Oncology, ranks among the top clinical oncology journals worldwide. ESMO events are the meeting place in Europe for medical oncologists to update their knowledge, to network and to exchange ideas. To find out more about ESMO, please visit: www.esmo.org

Abstract 42O_PR

ASSESSMENT OF GENETIC ALTERATIONS IN POSTMENOPAUSAL WOMEN WITH HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE ADVANCED BREAST CANCER FROM THE BOLERO-2 TRIAL BY NEXT-GENERATION SEQUENCING

M. Piccart1, H. Rugo2, D. Chen3, M. Campone4, H.A. Burris III5, T. Taran6, T. Sahmoud6, I. Deleu7, G. Hortobagyi8, J. Baselga9 

1Department Of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels/BELGIUM, 2Department Of Medicine, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco/UNITED STATES OF AMERICA, 3Department Of Global Oncology Development, Novartis Pharmaceuticals Corporation, Florham Park/UNITED STATES OF AMERICA, 4Centre De Recherche En Cancérologie, Institut de Cancérologie de l’Ouest, Nantes Saint Herblain/FRANCE, 5Drug Development, Sarah Cannon Research Institute, Nashville/UNITED STATES OF AMERICA, 6Department Of Global Oncology Development, Novartis Pharmaceuticals Corporation, East Hanover/UNITED STATES OF AMERICA, 7Department Of Medical Oncology, Breast Cancer Centre, AZ Nikolaas, Sint-Niklaas/BELGIUM, 8Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston/UNITED STATES OF AMERICA, 9Hematology/oncology, Memorial Sloan-Kettering Cancer Center, New York/UNITED STATES OF AMERICA

Introduction: In 724 postmenopausal women with HR+, HER2– advanced breast cancer, everolimus (EVE) plus exemestane significantly improved progression-free survival, response rate, and clinical benefit rate versus placebo plus exemestane (BOLERO-2 phase 3; NCT00863655; September 2012). Although benefits were seen in all prospectively defined subgroups, some variations were observed, partially due to genetic differences in molecular determinants of EVE sensitivity and interactions between the estrogen receptor (ER) and mTOR pathways.

Methods: Next-generation sequencing was used to comprehensively assess genetic alterations in archival tumor specimens. DNA was extracted and successfully analyzed from 230 tumors (>350 x coverage). Coding regions of 182 cancer-related genes were analyzed for sequence and copy number variations. Predicted germline event alterations were discarded.

Results: All patients had ≥1 genetic alteration; 98% had ≥2. 173 genes were altered in ≥1 tumor sample. Alteration number/sample varied (1-24; average, 9). Sequence variations (N = 1565) were primarily point mutations (85%), deletions (9%), and insertions (6%). Frequently mutated genes were PIK3CA (49%), TP53 (24%), and ARID1A (16%). ESR1, NF1, and IGFR1 mutations were seen in 9%, 5%, and 4% of samples, respectively. Of 112 patients with PIK3CA mutations, 55 and 43 had mutations in exon 20 and exon 9, respectively. PIK3CA and AKT1 (6%) mutations were mutually exclusive. Copy-number variations included 524 amplifications (most frequent: CCND1 [32%], FGFR1 [18%]) and 27 bi-allelic deletions. About 2/3 of samples had ≥1 amplification event. However, 10% of samples had ≥8 sequence variations but no gene amplification. Common mutation rates were comparable with those from the Cancer Genome Atlas. However, higher mutation frequencies were seen in some genes in BOLERO-2, likely due to the absence of germline variation data.

Conclusions: These results demonstrate the feasibility of large-scale sequencing in a phase 3 trial and generate potential hypotheses for developing targeted therapy combinations in this patient population.

Keywords: PIK3CA, breast cancer, BOLERO-2, genetic alterations