HER2 mutation as an emerging target in advanced breast cancer.

HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2-nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2-targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2-targeted drugs in HER2-mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges.

Breast and cervical cancer in transgender men: literature review and a case report.

Transgender individuals exhibit a higher prevalence of cancer-related risk factors, such as substance abuse and sexually transmitted infections. These factors, coupled with suboptimal adherence to cancer screening recommendations, may lead to a higher incidence of cancers, such as breast and cervical cancer, and contribute to delayed diagnoses in transgender patients. Herein, we report a unique case of a transgender man with a history of alcohol and drug abuse, undergoing gender-affirming exogenous testosterone therapy, who developed synchronous locally advanced breast cancer and human papilloma virus (HPV)-related cervical cancer. He underwent concurrent chemoradiation for cervical cancer and surgery followed by endocrine therapy for breast cancer. The treatments were suboptimals due to patient's comorbidities, among them liver cirrhosis leading to an early death. Additionally, we have conducted a review of existing literature, including case reports, clinical studies, and review articles investigating the role of potential risk factors specifically related to breast and cervical tumors in transgender men. Gender-affirming testosterone therapy is common among transgender men to induce gender affirmation, but its link to breast cancer risk remains ambiguous, with studies being limited and sometimes contradictory. Conversely, HPV is a well-established cause of up to 99% of cervical cancers. Despite persistent risk for cervical cancer in transgender men who retain their cervix, several studies indicate notable disparities in screening adherence, due to personal and structural barriers. Moreover, alcohol and drug use disorders, commonly encountered in transgender population, may negatively influence the adherence to screening programs. Current cancer screening guidelines for this population are somewhat unclear, and specific programs based on more robust data are urgently required along with further tailored studies.

Breast and cervical cancer in transgender men: literature review and a case report Transgender individuals are persons whose gender identity does not conform to that typically associated with the sex to which they were assigned at birth. Transgender people may have more cancer-related risk factors, such as substance abuse and sexually transmitted infections. These factors, along with suboptimal adherence to cancer screening, may lead to a higher incidence of cancers, among them breast and cervical cancer, and may also contribute to delayed diagnoses. Herein we report the case of a transgender man, recorded as female at birth but identifying as male, with a history of alcohol and drug abuse. He underwent testosterone therapy in order to affirm his gender. Moreover, he refused cancer screening, due to personal and social barriers. During the transition, he developed simultaneously a locally advanced breast cancer and a cervical cancer, the latter related to an infection from Human Papillomavirus. The patient was treated with chemoradiation for cervical cancer, and with surgery followed by endocrine therapy for breast cancer. The treatments were suboptimals due to patient's comorbidities, partly related to his previous lifestyle. Additionally, we have conducted a review of existing literature on the topic. Trangender men usually undergo testosterone to induce gender-affirmation. The role of testosterone therapy in breast cancer development remains unclear, with studies being contradictory. Conversely, Human Papillomavirus is a well-established cause of cervical cancers. Transgender men who retain their cervix are at risk for cervical cancer. Despite the persistent risk, notable disparities in screening adherence, due to personal and structural barriers, are reported. Moreover, alcohol and drug use disorders, commonly encountered in transgender population, may contrtibute to the low adherence to screening programs. Furthermore, screening guidelines are somewhat unclear, and specific programs are urgently required.

TRF2 as novel marker of tumor response to taxane-based therapy: from mechanistic insight to clinical implication.

BACKGROUND: Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) - the most aggressive BC form - is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients' response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy. METHODS: Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy. RESULTS: This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention. CONCLUSIONS: Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles' heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy.

DNA Damage Response in Early Breast Cancer: A Phase III Cohort in the Phobos Study.

We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D → EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical-pathological factors.

DARPP-32 and t-DARPP in the development of resistance to anti-HER2 agents. Pre-clinical evidence from the STEP study.

The therapeutic scenario of Human Epidermal Growth Factor Receptor 2 positive advanced breast cancer (ABC) has been recently enriched by a number of innovative agents, which are reshaping treatment sequence. While randomized trials have documented an advantage in terms of efficacy, for the newly available agents we lack effectiveness and tolerability evidence from the real-world setting. Similarly, the identification of predictive biomarkers might improve clinical decision. We herein describe the outline of a prospective/retrospective study which aims to explore the optimal sequence of treatment in HER2+, pertuzumab pre-treated ABC patients treated in II line with anti-HER2 agents in clinical practice. As part of the pre-clinical tasks envisioned by the STEP study, in vitro cell models of resistance were exploited to investigate molecular features associated with reduced efficacy of HER2 targeting agents at the transcript level. The aggressive behavior of resistant cell populations was measured by growth assessment in mouse models. This approach led to the identification of DARPP-32 and t-DARPP proteins as possible predictive biomarkers of efficacy of anti-HER2 agents. Biomarkers validation and the clinical goals will be reached through patients' inclusion into two independent cohorts, i.e., the prospective and retrospective cohorts, whose setup is currently ongoing.