Evaluation of multiple transcriptomic gene risk signatures in male breast cancer

Jane Bayani,Monika Nowaczyk,Carolien Van Deurzen,Coralie Poncet,John W.m Martens ,Florentine Hilbers,C Cunningham ,Sharon H Giordano,Kim Benstead,Oliver Bögler ,Monika Sobol,Tammy Piper,Elise Van Leeuwen-Stok,Ingrid Hedenfalk,Stéphanie Peeters ,Anouk Neven,Melissa P Murray ,D Van Den Weyngaert ,Cecilia Nilsson,Kathryn J Ruddy,Joanna Vermeij,Catherine M Kelly ,Lavinia P Middleton ,Larissa A Korde ,Barbro Linderholm,Judith Fraser,Fátima Cardoso ,Lissandra Dal Lago,Cheryl Crozier,Christi J Van Asperen ,Eric P Winer ,Carolien P Schröder ,Peggy L Porter ,Stefan Aebi,Aleksandra Peric,Isabel T Rubio,John M.s Bartlett

doi:10.1038/s41523-021-00301-0

Abstract

Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Several multigene assays are increasingly used to guide clinical treatment decisions in female BCa, however, there are limited data on the utility of these tests in male BCa. Here we present the gene expression results of 381 M0, ER+ve, HER2-ve male BCa patients enrolled in the Part 1 (retrospective analysis) of the International Male Breast Cancer Program. Using a custom NanoString™ panel comprised of the genes from the commercial risk tests Prosigna®, OncotypeDX®, and MammaPrint®, risk scores and intrinsic subtyping data were generated to recapitulate the commercial tests as described by us previously. We also examined the prognostic value of other risk scores such as the Genomic Grade Index (GGI), IHC4-mRNA and our prognostic 95-gene signature. In this sample set of male BCa, we demonstrated prognostic utility on univariate analysis. Across all signatures, patients whose samples were identified as low-risk experienced better outcomes than intermediate-risk, with those classed as high risk experiencing the poorest outcomes. As seen with female BCa, the concordance between tests was poor, with C-index values ranging from 40.3% to 78.2% and Kappa values ranging from 0.17 to 0.58. To our knowledge, this is the largest study of male breast cancers assayed to generate risk scores of the current commercial and academic risk tests demonstrating comparable clinical utility to female BCa.

Highlights

Male breast cancer (BCa) represents ~1% of all newly diagnosed cancers in men1 and ~1% of all breast cancers2
The use of molecular prognostic assays in female BCa is well established, but evidence relating to their performance in male BCa patients is sparse
In this study we show, using computational methods to recapitulate multiple BCa prognostic signatures, evidence for the prognostic impact of multiple gene signatures

Summary

Introduction

Male breast cancer (BCa) represents ~1% of all newly diagnosed cancers in men and ~1% of all breast cancers. Male breast cancer (BCa) represents ~1% of all newly diagnosed cancers in men and ~1% of all breast cancers2 Research into this rare disease has been limited, with treatment largely extrapolated from knowledge about female BCa3. Surgical management is usually modified radical mastectomy, with a minority of patients being offered breast conserving treatment. Local and systemic treatment is largely informed by treatment indications and regimens used in female breast cancer. For adjuvant endocrine treatment, the use of aromatase inhibitors (AIs) alone is not recommended, with tamoxifen for at least 5 years indicated for ER/PgR positive tumors. Where AIs are indicated, for example in metastatic male BCa, pituitary blockade with an LHRH agonist or orchiectomy is recommended

Methods

Results

Conclusion