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Breast, Lung Cancer Genetics Highlight Mutations Linked to Drug Response, Prognosis

NEW YORK (GenomeWeb) – A pair of new studies are continuing to spell out the somatic mutations that can provide clues to prognoses and/or drug response in specific forms of breast or lung cancer. 

For the first of the two studies, appearing online today in JAMA Oncology, researchers from the University of Melbourne and other centers in Australia, Switzerland, Italy, and the US searched for disease recurrence- and drug response-related alterations in early-stage, estrogen receptor-positive, HER2-negative forms of breast cancer treated with tamoxifen endocrine therapy and/or the aromatase inhibitor letrozole.

Using targeted sequence data for a subset of 764 ER+/HER- breast cancer cases profiled with a Foundation Medicine panel for Breast International Group (BIG) 1-98, a randomized Phase III clinical trial, the team searched for clinically informative alterations in almost 300 cancer-related genes.

"Although retrospective, our data are strengthened by the use of a clinical trial data set with prospective treatment randomization and robust recurrence data with a median follow-up of [eight] years," corresponding author Sherene Loi, a medical oncologist at the University of Melbourne's Peter MacCallum Cancer Centre, and her co-authors wrote.

Across the set of 538 breast cancer cases with sufficient sequence data, the researchers narrowed in on 19 somatic driver events found with at least 5 percent frequency in the tumor set. The most common changes — mutations affecting PIK3CA — showed significant ties to reduced distant recurrence risk, they reported.

In contrast, distant recurrence risk ticked up in tumors containing TP53 mutations, an overall rise in alterations affecting cancer driver genes, chromosome 11 amplifications, or amplifications involving portions of chromosomes. The amplification ties to recurrence remained significant after accounting for other prognostic factors in the team's subsequent multivariate analysis.

When it came to treatment response, meanwhile, the investigators noted that the presence of specific PIK3CA mutations in the breast tumors coincided with significantly improved letrozole response relative to tamoxifen response.

Based on their findings, the authors argued that "DNA-based classifications have promise to add to current prognostic markers and aid our adjuvant treatment decisions in ER+/HER2- disease."

In a related JAMA Oncology editorial, Vered Stearns and Ben Ho Park, with the Johns Hopkins School of Medicine's Sidney Kimmel Comprehensive Cancer Center, called the study "hypothesis generating."

"How and why certain PIK3Ca mutations predominate and whether there are differences in clinical outcomes in patients with different mutations remains unknown," Stearns and Park wrote, noting that aromatase inhibitor treatment is typically recommended for most post-menopausal women or pre-menopausal women with high-risk breast cancers.

"Women who receive tamoxifen likely have lower-risk tumors, cannot tolerate [aromatase inhibitors], or have a contraindication to [aromatase inhibitor] therapy," the pair explained. "Until additional data are available, PIK3CA mutational status should not be prospectively determined to guide adjuvant endocrine treatment recommendations."

In another JAMA Oncology study centered on lung squamous cell carcinoma cases treated with afatinib or erlotinib, an international team led by investigators at the University of Ottawa described treatment response-related mutations involving HER2 or other ERBB family genes.

For that analysis, the researchers relied on data from a randomized Phase III clinical trial called LUX-Lung8 that compared afatinib and erlotinib treatments for lung squamous cell carcinoma cases that advanced on or after several rounds of platinum-based chemotherapy treatment.

The team sent formalin-fixed, paraffin-embedded tumor samples from 245 of the lung squamous cell carcinoma cases from that trial to Foundation Medicine for genetic profiling with FoundationOne, searching for frequent mutations, copy number changes, or rearrangements affecting hundreds of genes, including ERBB representatives.

"Given that afatinib irreversibly inhibits signaling from all homodimers and heterodimers of the ERBB family and that these receptors cooperate via interconnected intracellular pathways to regulate cellular proliferation, it is possible that genetic aberrations within the family might identify a subgroup of patients who could particularly benefit from afatinib treatment," the authors explained.

The tumors taken forward for profiling were enriched for cases with relatively good progression-free survival outcomes, they noted. For 345 tumors, including 11 of those assessed genetically, the investigators obtained EGFR immunohistochemical profiles.

Overall, the team saw enhanced survival times in the genetically profiled, afatinib-treated group: 3.5 months progression-free survival, as a median, compared to median progression-free survival of 2.5 months in the group treated with erlotinib and a median of 8.4 months overall survival (compared to a median of 6.6 months in the erlotinib arm).

Both progression-free and overall survival times were stretched out further in the 53 afatinib-treated individuals with ERBB gene family mutations such as HER2 mutations in their tumors — a survival association that was not detected for EGFR levels or copy number changes in the tumor set.

"We hypothesize that the additional benefit with afatinib is attributable to its broad, irreversible inhibition of the entire ERBB signaling network," corresponding author Glenwood Goss, a medical oncology researcher at the Ottawa Hospital Research Institute, and his colleagues concluded, adding that afatinib "may be particularly suitable for [lung squamous cell carcinoma] patients whose tumors carry at least [one] ERBB mutation."

University of California at Davis researchers David Gandara, Jonathan Riess, and Primo Nara Jr. noted that "[a]lthough the benefits of treatment with afatinib in the previously reported intent-to-treat population were modest for both progression-free survival and overall survival, the analysis by Goss et al. reveals that efficacy was magnified among afatinib-treated patients with underlying ERBB mutations [versus] those without, an effect not observed among the corresponding erlotinib-treated cohorts."

In another JAMA Oncology commentary article, the authors cautioned that the prognoses for these lung squamous cell carcinoma patients remained relatively poor, even with the ERBB gene family mutation-related boost in outcomes.

Still, they said, "treatment with afatinib appears to be a reasonable option as second- or third-line therapy dependent on the initial treatment regimen" for ERBB-mutated lung squamous cell carcinomas, particularly when alternative targeted treatments are lacking.