Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis. The current first-line treatment for advanced TNBC (aTNBC) is determined by the expression of programmed cell death-ligand 1 (PD-L1). In the ATRACTIB trial—a multicenter, single-arm, phase 2 study—we evaluated the combination of atezolizumab, paclitaxel and bevacizumab as first-line treatment for patients with aTNBC, independently of PD-L1 status. The primary endpoint was investigator-assessed progression-free survival. One hundred female patients were enrolled, with most evaluable tumors being PD-L1-negative (97.6%). The primary endpoint was met, with a median progression-free survival of 11.0 months (95% confidence interval (CI): 9.0–13.4; P < 0.001). The objective response rate was 63.0% (95% CI: 52.8–72.4) and median overall survival was 27.4 months (95% CI: 23.4–37.4). No treatment-related deaths or new safety signals were observed. This combination demonstrated significant antitumor activity as first-line therapy for aTNBC patients and merits further investigation. ClinicalTrials.gov Identifier: NCT04408118.

Purpose of Review: Extramammary Paget disease (EMPD) is a rare entity which is more frequently localized at the vulva, though it only accounts for 1–2% of vulvar neoplasms. It is a primary cutaneous adenocarcinoma whose cell of origin is still a matter of controversy: it can either arise from apocrine/eccrine glands or from stem cells. The diagnosis demands a biopsy and entails a histopathological analysis by which cells show similar characteristics as breast Paget disease. Recent Findings: Treatment approach can entail surgery, radiotherapy, photodynamic therapy, systemic chemotherapy, and topical chemotherapy. For metastatic disease, many different chemotherapy regimens have been explored and even targeted therapy can play an important role in this disease. Since almost 30–40% of patients overexpress HER-2, trastuzumab and anti-HER-2 therapies can be employed in this setting. Summary: Due to its low incidence, there is almost no specific evidence on therapeutic interventions for this disease. Thus, there is a neat unmet need for molecular characterization of EMPD and diagnostic tools that allow clinicians to guide treatment both in the early and in the advanced disease settings. In this review, we aim to summarize available evidence about diagnosis and treatment of EMPD, both localized and metastatic, and to provide a comprehensive analysis that may help clinicians for therapeutic decisions.

Background: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)‐low‐expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset.Methods: Women aged ≤40 years with newly diagnosed early‐stage HER2‐negative BC (HER2‐0 and HER2‐low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi‐square test and Student t‐test were used to describe variable distribution between HER2‐0 and HER2‐low. Associations with HER2‐low status were assessed with logistic regression. Kaplan–Meier method and Cox regression analysis were used to assess disease‐free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05.Results: Of 3547 included patients, 32.3% had HER2‐low BC, representing 46.3% of hormone receptor–positive and 21.3% of triple‐negative (TN) tumors. HER2‐low vs. HER2‐0 BC were more often of grade 1/2 (p < .001), hormone receptor–positive (p < .001), and node‐positive (p = .003). BRCA2 PVs were more often associated with HER2‐low than BRCA1 PVs (p < .001). HER2‐low versus HER2‐0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76–0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64–0.95) and overall survival (HR, 0.65; 95% CI, 0.46–0.93) in the TN subgroup. Luminal A–like tumors in HER2‐low (p = .014) and TN and luminal A‐like in HER2‐0 (p = .019) showed the worst DFS.Conclusions: In young patients with HER2‐negative BC and germline BRCA1/2 PVs, HER2‐low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal‐like disease. HER2‐low status was associated with a modestly improved prognosis.

Background: The characterization of molecular alterations of primary breast carcinomas (BC) and their cutaneous metastases (CM) to identify genes involved in the metastatic process have not yet been completely accomplished. Methods: To investigate the molecular alterations of BC and their CM, a total of 66 samples (33 BC and 33 CM) from 33 patients were analyzed by immunohistochemical and massive parallel sequencing analyses. In addition, the clinicopathological characteristics of patients and tumors were analyzed. Results: Triple negative (TN) BCs were overrepresented (36.4%) among tumors that developed CM. A change of tumor surrogate molecular type in metastases was found in 15% of patients and 48.5% of the CM presented some additional molecular alteration with respect to the primary tumor, the most frequent were amplification of MYC and MDM4, and mutations in TP53 and PIK3CA. Survival was related to histological grade, tumor surrogate molecular type and TP53 mutations in the univariate analysis but only the tumor surrogate molecular type remained as a prognostic factor in the multivariate analysis. Conclusions: The TN molecular type has a greater risk of developing skin metastases. There are phenotypic changes and additional molecular alterations in skin metastases compared to the corresponding primary breast tumors in nearly half of the patients. Although these changes do not follow a specific pattern and varied from patient to patient, they could impact on the treatment. More studies with larger patient and sample cohorts are needed.

In this study, molecular alterations in endometrial carcinoma (EC) recurrences were analyzed. We aimed to identify genes implicated in tumor progression and to evaluate whether histologic and molecular type shifting occurs in recurrences. Thus, we analyzed 50 samples corresponding to 24 primary ECs (15 low-grade endometrioid endometrial carcinomas [LG-EECs] and 9 high-grade endometrial carcinomas) and their corresponding 26 recurrences. These were studied by immunohistochemistry, next-generation sequencing, and MLH1 promoter methylation. We observed shared mutations in all primary tumors and their recurrences, indicating a clonal relationship between both lesions. Most morphologic and molecular changes associated with progression were found in LG-EEC. In this group, 6 patients (40%) presented additional mutations in the recurrence. These mutations more frequently affected genes of the PI3K/AKT/PTEN pathway, implicating this pathway not only in tumor initiation but also in progression. In addition, 2 patients (13%) in which the primary tumor belonged to the nonspecific molecular profile subtype, shifted to the mismatch repair deficient (MMRd) subtype after the acquisition of MLH1 promoter methylation in the recurrence lesions. In 3 patients (20%) with MMRd, there was a change from LG-EEC to G3-EEC. One TP53-mutated LG-EEC transformed into an undifferentiated carcinoma in a mediastinal lymph node metastasis after losing the expression of SMARCA2 while preserving SMARCA4 and SMARCB1. Morphologic and molecular changes in EC recurrences, especially dedifferentiation and the acquisition of MMRd, should be considered for a correct diagnosis and treatment. MMRd should be tested in metastatic lesions, if available, in patients with primary tumors reported to be of a molecular subtype different from MMRd.

Background: Luminal advanced breast cancer (ABC) patients eventually progress on endocrine therapy. REVERT aimed to explore whether eribulin could restore endocrine sensitivity in a randomized, non-comparative phase II trial. Methods: Aromatase inhibitor (AI)-resistant patients with luminal ABC were randomized 1:1 to receive eribulin +/− AI. Patients were stratified by prior cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) treatment. The primary endpoint was an investigator-assessed overall response rate (ORR) according to RECIST version 1.1 in the eribulin + AI arm. An interim analysis was planned with 11 evaluable patients according to a two-stage Simon design. Results: Twenty-two patients were enrolled (15 eribulin + AI arm; 7 eribulin arm). The trial was terminated early in March 2021, with eight (36.4%) patients still on treatment. ORR was 26.7% in the eribulin + AI arm (95% CI, 7.8–55.1%; p = 0.0541). In the eribulin arm, two (28.6%) patients had an objective response (95% CI, 3.7–71.0%). The difference between the study arms was not significant (p = 0.918). The addition of AI to eribulin also failed to show improvement in other efficacy endpoints. A significant interaction between the treatment arm and previous CDK4/6i treatment was observed for ORR (p = 0.018) and progression-free survival (p = 0.084). Overall, the toxicity profile was consistent with the known safety profile of eribulin. No treatment-related deaths were reported. Conclusion: Eribulin + AI does not seem to improve outcomes compared with eribulin monotherapy in patients with AI-resistant luminal ABC. This chemo–endocrine approach deserves further investigation after progression to CDK4/6i-based therapy.