Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance

Zelli, Veronica; Silvestri, Valentina; Valentini, Virginia; Bucalo, Agostino; Rizzolo, P.; Zanna, Ines; Bianchi, Simonetta; Coppa, Anna; Giannini, Giuseppe; Cortesi, Laura; Calistri, Daniele; Tibiletti, Maria Grazia; Fox, Stephen B.; Fab, kCon; Palli, Domenico; Ottini, Laura

doi:10.3390/cancers13184515

Cited by 7 publications

(5 citation statements)

References 38 publications

(56 reference statements)

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“…Moreover, transcriptomic data on MBC showed that male breast tumors associated with germline BRCA1/2 PVs and those with a high immune involvement were also characterized by a high HER2 signaling score, despite being classified as HER2-negative by IHC, suggesting that the HER2 pathway may be active [32][33][34]; thus, they might benefit from treatment with T-DXd, or from a combined therapeutic approach including PARPi and/or immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy

Silvestri,

Valentini,

Bucalo

et al. 2024

Cancers

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In the field of breast cancer care, a significant breakthrough has occurred with the recognition of HER2-low expression as a target for novel anti-HER2 antibody–drug conjugates (ADC). This discovery is reshaping the treatment landscape, challenging previous perceptions that considered HER2-low as clinically insignificant. The ability to target HER2-low expression is expected to have substantial clinical implications, irrespective of gender, including in cases of male breast cancer (MBC). However, an estimate of the prevalence of the HER2-low subtype in MBC is missing. This retrospective, observational, multicenter study was aimed at characterizing the HER2-low subtype in MBC. For the purpose of this study, the three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) was used to reclassify the HER2-negative group into HER-0 or HER2-low subtypes. In the whole series of 144 invasive MBCs, 79 (54.9%) were HER2-0 (IHC scores of 0), 39 (27.1%) HER2-low (IHC scores of 1+/2+ with negative ISH), and 26 (18.0%) HER2-positive (IHC scores of 3+/2+ with positive ISH). Specifically, among hormone receptor-positive (HR+) HER2-negative invasive MBCs, 34.8% were HER2-low and 65.2% HER2-0. Compared with HER2-0, HER2-low subtype was associated with a positive lymph node involvement (p = 0.01). Other pathologic characteristics including histology, staging, and grading did not show notable variations between the two subtypes. The presence of germline BRCA1/2 pathogenic variants (PVs) did not significantly differ between HER2-0 and HER2-low MBCs. However, about 13% of HER2-low MBCs had germline PVs in BRCA1/2 genes, mainly BRCA2, a clinically relevant observation in the context of combined target therapy. Overall, our data, which focused on the largest gender-specific breast cancer series, to our knowledge, confirm that the emerging three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) can also be considered in MBC, to mitigate both the gender gap and the underrepresentation of males in clinical trials.

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Section: Discussionmentioning

confidence: 99%

HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy

Silvestri,

Valentini,

Bucalo

et al. 2024

Cancers

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“…Zelli et al did an RNA sequencing analysis of 63 MBCs and found out that DNA damage and repair genes BARD1, BRIP1, and XRCC2 and cell cycle regulation genes FOXM1 and AURKA were significantly upregulated in germlinemutated MBCs compared to nonmutated MBCs. Higher proliferation and HER2 signalling module scores were observed in germline-mutated MBCs [14].…”

Section: Geneticsmentioning

confidence: 92%

Male Breast Cancer: An Updated Review of Patient Characteristics, Genetics, and Outcome

Khare,

Huda,

Misra

et al. 2024

International Journal of Breast Cancer

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Male breast cancer (MBC) is a rare entity, underrepresented in population studies and clinical trials, resulting in management of MBC to be informed by current research on female breast cancer (FBC). A literature review was conducted by accessing relevant articles on 2 databases, by searching keywords “male breast cancer”. A total of 29 articles from year 2011 to 2022 were selected for this review. The authors found that male breast cancer generally occurs later in life with higher stage, higher grade, and more estrogen receptor (ER) positive tumours. Most of the studies noted the mean age for MBCs at the time of presentation as >60 years. Risk factors for male breast cancer include family history, obesity, lower physical activity, and syndromes like the Klinefelter syndrome. Positive family history is much higher in MBC compared to FBC (30.9 vs. 18.4%). BRCA 2 cancers constitute a higher proportion compared to FBCs. A lot of genetic mutations have been observed. Some show promise to assess disease-specific survival and proliferative rate like TWIST1 and RUNX3, among others. MBCs usually present with a palpable lump in central region, with a bigger size and chance of nodal involvement and metastasis compared to FBCs. They are mostly infiltrating ductal type and hormone receptor positive, with worse histological grade. Treatment usually follows the same principles as FBCs (systemic therapy, surgical excision, and radiotherapy), with poorer prognosis to same treatment approach, possibly owing to its advanced stage at presentation. This is a rare entity which requires further research to ascertain need for different management approach than FBCs.

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“…It is well established that FBC can be classified into molecular subtypes based on gene expression, with BRCA1-mutated tumors showing a prevalence in the basal-like subtype, while BRCA2-mutated FBC may show gene expression patterns that resemble those found in luminal epithelial cells [205][206][207]. Recent transcriptome data on MBC indicate that germline mutational status could impact also on MBC transcriptome profiles, defining subgroups that may be driven by different underlying molecular pathways [208]. Specifically, male breast tumors arising in patients with germline PVs in BRCA and PALB2 were characterized by the activation of the cell cycle pathway, suggesting a possible use of CDK4/6 inhibitors in this setting.…”

Section: Personalized Therapeutic Managementmentioning

confidence: 99%

“…It was recently shown that BRCA2 PVs may affect the tumor microenvironment differently than BRCA1 PVs, and that BRCA2-associated tumors might respond better to checkpoint blockade immunotherapy [227]. Immune response recently emerged as the most relevant process able to discriminate MBC subgroups at the transcriptional level, particularly in BRCA-associated MBCs [208], opening for further investigation of immune-related features in a subgroup of male breast tumors.…”

Section: Personalized Therapeutic Managementmentioning

confidence: 99%

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

Valentini,

Bucalo,

Conti

et al. 2024

Cancers

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Among neoplastic diseases, breast cancer (BC) is one of the most influenced by gender. Despite common misconceptions associating BC as a women-only disease, BC can also occur in men. Additionally, transgender individuals may also experience BC. Genetic risk factors play a relevant role in BC predisposition, with important implications in precision prevention and treatment. The genetic architecture of BC susceptibility is similar in women and men, with high-, moderate-, and low-penetrance risk variants; however, some sex-specific features have emerged. Inherited high-penetrance pathogenic variants (PVs) in BRCA1 and BRCA2 genes are the strongest BC genetic risk factor. BRCA1 and BRCA2 PVs are more commonly associated with increased risk of female and male BC, respectively. Notably, BRCA-associated BCs are characterized by sex-specific pathologic features. Recently, next-generation sequencing technologies have helped to provide more insights on the role of moderate-penetrance BC risk variants, particularly in PALB2, CHEK2, and ATM genes, while international collaborative genome-wide association studies have contributed evidence on common low-penetrance BC risk variants, on their combined effect in polygenic models, and on their role as risk modulators in BRCA1/2 PV carriers. Overall, all these studies suggested that the genetic basis of male BC, although similar, may differ from female BC. Evaluating the genetic component of male BC as a distinct entity from female BC is the first step to improve both personalized risk assessment and therapeutic choices of patients of both sexes in order to reach gender equality in BC care. In this review, we summarize the latest research in the field of BC genetic predisposition with a particular focus on similarities and differences in male and female BC, and we also discuss the implications, challenges, and open issues that surround the establishment of a gender-oriented clinical management for BC.

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Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance

Cited by 7 publications

References 38 publications

HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy

HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy

Male Breast Cancer: An Updated Review of Patient Characteristics, Genetics, and Outcome

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

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