Certain molecular changes in breast cancer genes occurred more often in metastatic disease, possibly suggesting new strategies for difficult-to-treat disease, according to initial data from an ongoing study.

Matched tissue specimens from primary tumors and metastases showed higher rates of mutations in driver genes and variations in gene copy number in metastatic breast cancer (MBC). Metastases also had fewer immune-related genes and a different immune-cell composition, which could help make the tumor microenvironment more favorable to development of metastases.

More than half of 381 patients analyzed so far had molecular changes for which targeted therapies already exist, Martine Piccart, MD, PhD, of Jules Bordet Institute in Brussels, Belgium, and colleagues reported in Cancer Discovery.

Taken together, the findings highlight “the potential impact of molecular screening in the management of MBC,” according to a statement from the institute, Frontier Science, and the Breast International Group (BIG), which is sponsoring the AURORA study of molecular screening in MBC.

“Molecular alterations found to be enriched in AURORA metastatic samples could contribute to new drug development for MBC,” Piccart and colleagues stated in the journal article.

“Beyond the findings discussed in the manuscript, the AURORA initiative is providing the basis for future research in MBC …” they added. “The curated clinical database, as well as the central store of pathology high-resolution scanned images, the collection of clinical data including the identification of outlier patients — exceptional responders or with highly resistant disease — that will be studied in-depth could allow us to generate hypotheses for novel therapeutic strategies.”

Despite substantial improvement in breast cancer survival, the disease remains a leading cause of cancer-related mortality in women, with metastatic progression leading the way. The dominant role of metastasis in breast cancer mortality highlights the need for treatment strategies that prevent metastatic relapse and improve outcomes for patients with de novo metastatic disease, the authors noted.

Efforts to improve treatment of MBC have focused primarily on empirical evaluation of treatment strategies in different breast cancer subtypes, primarily hormone receptor-positive/HER2-negative, HER2-positive, or triple-negative breast cancer.

“Consequently, treatment decisions are dictated by these limited subtypes, and the lines of therapy rely on minimal biological data,” the authors noted.

Against the preceding background, BIG initiated the AURORA molecular screening program to improve understanding of MBC by means of extensive profiling of paired primary tumors and samples of metastases. The pan-European research effort has a goal of performing genomic analyses of paired samples of primary tumors and metastases from a minimum of 1,000 patients with MBC. Analyses include tumor specimens and circulating tumor DNA.

The 381 patients included in the initial report came from 51 centers in nine countries. Analyses were based on targeted gene sequencing in 252 cases, RNA sequencing in 152, and single nucleotide polymorphism (SNP) arrays in 67. With regard to breast cancer subtype, 247 (65%) patients had HR-positive/HER2-negative tumors, 72 (19%) had TNBC, and 60 (16%) had HER2 breast cancer. Almost a fourth (23%) of the patients had de novo MBC.

Overall, 88% of point mutations in driver genes occurred in both the primary tumor and the metastasis. In 10% of cases, at least one point mutation was acquired in metastases. Metastases were enriched with point mutations in ESR1, PTEN, CDH1, PIK3CA, and RB1. SNP analysis identified copy-number variants in 31% of the metastases. Metastatic lesions more often had copy number gains of MEM4, MYC, NSD3, FGF41, AXIN1, TSC2, FLT4, NTRK1, and N4BP2, as well as deletions of ARHGEF10L, CASP9, RB1, ARID1A, and PBRM1.

AURORA has already generated what is thought to be the largest dataset of RNA sequencing in MBC, the authors said. The data showed that breast cancer intrinsic subtype changed in 36% of cases from primary to metastatic specimen. In general, the change reflected transition to a more aggressive subtype, an observation that may have treatment implications, they added.

A preliminary analysis of factors influencing survival showed that women with HR-positive/HER2-negative breast cancer and high tumor mutational burden (TMB) in the primary tumor had shorter survival and shorter time to relapse, suggesting TMB is an independent predictor of poor prognosis.

As a final key observation highlighted by the investigators, 193 (51%) of patients had molecular alterations that could be targeted by an existing therapy. Nonetheless, only 7% of the patients received matched therapy, some of which can be explained by drug availability, as the study began in 2014, and heterogeneous access to clinical trials.