Diverse Genetic Alterations Found in Triple-negative Breast Cancers After Neoadjuvant Chemotherapy

Released: 28-Nov-2012 1:00 PM EST
Embargo expired: 6-Dec-2012 8:30 AM EST
Source Newsroom: CRRC-AACR San Antonio Breast Cancer Symposium
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This abstract will be presented at a press conference hosted by Carlos L. Arteaga, M.D. associate director for clinical research and director of the Breast Cancer Program at Vanderbilt Ingram Cancer Center, on Thursday, Dec. 6 at 7:30 a.m. CT in Room 217 A-C of the Henry B. Gonzales Convention Center. Reporters who cannot attend in person can call in using the following information:
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Newswise — SAN ANTONIO — Many different genetic alterations were detected in tumor cells left behind after patients with triple-negative breast cancer were treated with chemotherapy prior to surgery (neoadjuvant chemotherapy), according to data presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, held here Dec. 4-8. The investigators hope this knowledge will help move toward early personalized treatment to combat this aggressive subtype of breast cancer.

“The standard of care for many patients with triple-negative breast cancer is to administer chemotherapy before surgery to shrink the tumor,” said Justin M. Balko, Pharm.D, Ph.D., research faculty who led this study in the laboratory of Carlos Arteaga, M.D., at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

“Unfortunately, about 70 percent of patients still have some residual disease at the time of surgery, despite treatment,” Balko said. “We speculate this residual disease in the breast should look just like simultaneous micrometastases that are destined to recur in the same patient. Thus, we need to know what is in this tissue that is left behind to conceive targeted therapies to treat and prevent recurrence of metastases down the road.”

Balko and colleagues profiled residual tumor tissue from 102 patients with triple-negative breast cancer who had received neoadjuvant chemotherapy. In DNA from 89 evaluable tumors, the investigators used deep sequencing to examine 182 oncogenes and tumor suppressors that are known to be altered in human cancers. Instead of finding similar genes affected among the patients, they found a diverse set of genes were altered.

“We already knew that triple-negative breast cancer is driven by a diverse group of genetic alterations,” said Balko. “So, in one way, we fell further down this rabbit hole, but we also found some things that could be promising therapeutically, such as frequent MYC, MCL1 and JAK2 amplifications as well as mutations in the PI3K pathway.”

According to Balko, the next step is to confirm the findings in a larger patient cohort, and if the findings are replicated, broad molecular approaches will be needed to help inform personalized therapies for triple-negative breast cancer. Furthermore, it will be necessary to explore the therapeutic sensitivity of breast cancers harboring these lesions in the laboratory to know how to treat patients with breast cancer who have these alterations.

This research was a collaboration of the Breast Cancer Research Program at Vanderbilt, the Instituto Nacional de Enfermedades Neoplásicas (Lima, Perú) and Foundation Medicine (Cambridge, Mass.). It was funded by the Susan G. Komen for the Cure Foundation, the National Institutes of Health (Vanderbilt Breast SPORE Grant P50 CA98131) and the Lee Jeans/Entertainment Industry Foundation Translational Breast Cancer Research Program.

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The mission of the CTRC-AACR San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR) and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR’s scientific prestige in basic, translational and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit www.sabcs.org.

Abstract:
Publication Number: S3-6

Title: Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in the treatment-refractory residual disease

Justin M Balko1, Kai Wang2, Melinda E Sanders1, Maria G Kuba1, Joseph A Pinto3, Franco Doimi4, Henry Gomez4, Gary Palmer2, Maureen T Cronin2, Vince A Miller2, Roman Yelensky2, Phil J Stephens2 and Carlos L Areaga1. 1Vanderbilt University, Nashville, TN; 2Foundation Medicine, Cambridge, MA; 3Oncosalud, Lima, Peru and 4Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.

Body: Background: Neoadjuvant chemotherapy (NAC) is increasingly used in patients with triple-negative breast cancer (TNBC). NAC can induce a pathologic complete response (pCR) in 30% of patients which portends a favorable prognosis. In contrast, patients with residual disease (RD) in the breast at surgical resection exhibit worse outcomes.

Objective: We hypothesized that profiling residual TNBCs after NAC would identify molecularly targetable lesions in the chemotherapy-resistant component of the tumor and that the persistent tumor cells would mirror micro-metastases which ultimately recur in such patients.

Methods: We utilized targeted next generation sequencing (NGS) for 182 oncogenes and tumor suppressors in a CLIA certified lab (Foundation Medicine, Cambridge, MA) and gene expression profiling (NanoString) of the RD after NAC in 102 patients with TNBC. The RD was stained for Ki67, which has been reported to predict outcome after NAC in unselected breast cancers.

Results: Thirteen tumors were not evaluable due to low tumor cellularity. Of 89 evaluable post-NAC tumors, 57 (64%) were basal-like; 19% HER2-enriched; 6% luminal A; 6% luminal B and 5% normal-like. Mean depth of coverage was 635 (range: 135-1207). Of 81 tumors evaluated by NGS, 72/81 (89%) demonstrated mutations in TP53, 22 were MCL1-amplified (27%), and 17 were MYC-amplified (21%). Alterations in the PI3K/mTOR pathway (AKT1-3, PIK3CA, PIK3R1, RAPTOR, PTEN, and TSC1) were identified in 27 tumors (33%). Cell cycle genes were altered in 25 tumors (31%), including amplifications of CDK2, CDK4,and CDK6, CCND1-3, and CCNE1 as well as RB loss. Alterations in the DNA repair pathway (BRCA1/2, ATM; 16 tumors; 20%) and the Ras/MAPK pathway (KRAS, RAF1, NF1; 10 tumors; 12%) were also common. Sporadic growth factor receptor amplifications occurred in EGFR, KIT, PDGFRA, PDGFRB, MET, FGFR1, FGFR2, and IGF1R. NGS identified 7 patients with ERBB2 gene amplification in the RD which was confirmed by FISH in both the pre- and post-treatment tissue, suggesting NGS could assist in the identification of ERBB2-overexpressing tumors misclassified at the time of diagnosis. In general, the gene amplifications identified by NGS corresponded to enhanced gene expression levels. Amplifications of MYC were independently associated with poor recurrence-free survival (RFS) and overall survival (OS). An interaction effect on survival was observed between MEK activation (assayed by a gene expression signature) and MYC amplification, suggesting cooperation between these pathways. Alterations in DNA repair also identified a subgroup with poor RFS and OS. In contrast, high post-NAC Ki67 score did not predict poor RFS or OS in this predominantly TNBC cohort.

Conclusions: The diversity of lesions in residual TNBCs after NAC underscores the need for powerful and broad molecular approaches to identify actionable molecular alterations and, in turn, better inform personalized therapy of this aggressive disease. Incorporation of this platform into clinical studies and eventually standards of care should aid in the prioritization of patients with RD after NAC into rational adjuvant studies.


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