Molecular changes may guide treatment for metastatic breast cancer

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

Paired tissue samples from primary tumors and metastases showed higher rates of motor gene mutations and gene copy number variations in metastatic breast cancer (MBC). The metastases also had fewer genes related to the immune system and a different immune cell composition, which could help make the tumor microenvironment more conducive to the development of metastases.

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

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

“The molecular alterations found enriched in AURORA metastatic samples could contribute to the development of new drugs for MBC,” Piccart and colleagues said in the journal article.

“Beyond the results discussed in the manuscript, the AURORA initiative provides the basis for future research on MBC …”, they added. “The organized clinical database, as well as the central store of high-resolution scanned pathology images, the collection of clinical data, including the identification of aberrant patients – exceptional responders or highly resistant disease – that will be investigated in depth could allow us to generate hypotheses for new therapeutic strategies. “

Despite a substantial improvement in breast cancer survival, the disease remains a major cause of cancer-related death 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 the treatment of MBC have primarily focused on the empirical evaluation of treatment strategies in different breast cancer subtypes, primarily hormone receptor positive / HER2-negative, HER2-positive, or triple-negative.

“Therefore, treatment decisions are driven by these limited subtypes, and treatment lines are based on minimal biological data,” the authors noted.

In the previous context, BIG initiated the AURORA molecular screening program to improve understanding of MBC through extensive profiling of paired primary tumors and metastasis samples. The pan-European research effort aims to perform genomic analyzes of matched samples of primary tumors and metastases from a minimum of 1,000 patients with CBM. Analyzes include tumor samples and circulating tumor DNA.

The 381 patients included in the initial report were from 51 centers in nine countries. Analyzes were based on targeted gene sequencing in 252 cases, RNA sequencing in 152, and single nucleotide polymorphism (SNP) arrays in 67. Regarding 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 quarter (23%) of patients had de novo MBC.

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

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

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 relapse period, suggesting that TMB is an independent predictor of poor prognosis.

The last key observation highlighted by the researchers, 193 (51%) of the patients presented with molecular alterations that could be targeted by an existing therapy. However, only 7% of patients received appropriate therapy, some of which can be explained by the availability of drugs, since the study began in 2014, and heterogeneous access to clinical trials.

  • Charles Bankhead is Editor-in-Chief for Oncology and also covers Urology, Dermatology and Ophthalmology. He joined MedPage Today in 2007. To pursue

Disclosures

The study was supported by the Breast Cancer Research Foundation, with additional contributions from several public and private organizations and foundations, as well as individual donors.

Piccart disclosed relationships with Oncolytics, AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, HUYA, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Periphagen, Pfizer, Roche, Seattle Genetics, Radius, Servier and Synthon.



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