Background: The treatment landscape in HR+/HER2− metastatic breast cancer (mBC) is continuously evolving, with evidence on new agents and combinations published almost every year. Despite updated therapeutic guidelines, second-line (2L) selection may be challenging due to clinical factors, biomarker status, and available agents. Methods: A two-round Delphi consensus was organized in July 2024, gathering input from 10 experts in research, diagnosis, and treatment of HR+/HER2− mBC on optimal 2L and beyond choice, considering the available biomarkers and results from published clinical trials. Consensus was defined as 70% agreement or disagreement. Results: The experts considered initially a list of 39 statements, structured into the following four sections: biomarker testing; selection of 2L treatment at progression of disease on first line endocrine therapy (ET) + CDK4/6i at ≥6 months after initiation of ET for mBC; selection of 2L treatment at disease progression on ET + CDK4/6i, at <6 months after initiation of ET for mBC, whilst on ET; and selection of post-2L treatment options. After a discussion, the experts decided to remove four statements, refine ten, and include three new ones. The final list consisted of 38 statements, and consensus was achieved in 37. Conclusions: The panel recommends next-generation sequencing as the method of choice for genomic characterization at disease progression on first line. The optimal agent or treatment class is indicated depending on the presence of specific mutations; however, the panel admits that the strategy is different in clinical practice, where novel therapies might not be available or reimbursed.

High infiltration by tumor-infiltrating lymphocytes (TILs) is associated with favorable prognosis in different tumor types, but the clinical significance of their spatial localization within the tumor microenvironment is debated. To address this issue, we evaluated the accumulation of intratumoral TILs (itTILs) and stromal TILs (sTILs) in samples from 97 patients with early triple-negative breast cancer (TNBC) in the center (sTIL central) and periphery (sTIL peripheral) of tumor tissues. Moreover, the presence of primary and secondary lymphoid aggregates (LAs) and the expression levels of the cancer testis antigen (CTA), NY-ESO-1, and PD-L1 were explored. High infiltration by itTILs was observed in 12/97 samples (12.3%), unrelated to age, Ki67 expression, tumor size, histologic type and grade, and LA presence. NY-ESO-1 was expressed in tumor cells in 37 samples (38%), with a trend suggesting a correlation with itTIL infiltration (p = 0.0531). PD-L1 expression was detected in immune cells in 47 samples (49%) and was correlated with histologic grade, sTILs, and LA formation. The presence of primary LAs was significantly correlated with better disease-free survival (DFS) (p = 0.027). Moreover, no tumor progression was observed during >40 months of clinical follow up in the 12 patients with high itTILs or in the 14 patients with secondary LAs. Thus, careful evaluation of lymphoid infiltrate intratumoral localization might provide important prognostic information.

“Basal-like” (BL) morphology and the expression of cancer testis antigens (CTA) in breast cancer still have unclear prognostic significance. The aim of our research was to explore correlations of the morphological characteristics and tumor microenvironment in triple-negative breast carcinomas (TNBCs) with multi-MAGE-A CTA expression and to determine their prognostic significance. Clinical records of breast cancer patients who underwent surgery between January 2017 and December 2018 in four major Croatian clinical centers were analyzed. A total of 97 non-metastatic TNBCs with available tissue samples and treatment information were identified. Cancer tissue sections were additionally stained with programmed death-ligand 1 (PD-L1) Ventana (SP142) and multi-MAGE-A (mAb 57B). BL morphology was detected in 47 (49%) TNBCs and was associated with a higher Ki-67 proliferation index and histologic grade. Expression of multi-MAGE-A was observed in 77 (79%) TNBCs and was significantly associated with BL morphology. Lymphocyte-predominant breast cancer (LPBC) status was detected in 11 cases (11.3%) and significantly correlated with the Ki-67 proliferation index, increased number of intratumoral lymphocytes (itTIL), and PD-L1 expression. No impact of BL morphology, multi-MAGE-A expression, histologic type, or LPBC status on disease-free survival was observed. Our data suggest that tumor morphology could help identify patients with potential benefits from CTA-targeting immunotherapy.

We report a rare case of simultaneous well-differentiated papillary mesothelial tumor (WDPMT) and multicystic mesothelioma. The concurrent occurrence of these entities is exceptionally uncommon and may pose challenges during surgical intervention. Both tumors are variants of epithelioid mesothelioma and are most frequently identified incidentally during surgical procedures. A 41-year-old patient was admitted for laparoscopic surgery due to a left adnexal mass. Ultrasound examination revealed a 5 cm lesion adjacent to the left ovary, exhibiting central vascularization. Intraoperatively, the mass appeared as a solid, soft, and nodular tumor. Frozen section analysis confirmed the diagnosis of WDPMT involving the left adnexa. Recognition of well-differentiated papillary mesothelial tumor and multicystic mesothelioma is critical for accurate differential diagnosis from malignant mesothelioma. Awareness of these entities informs appropriate surgical management and follow-up protocols.

We report a rare case of simultaneous well-differentiated papillary mesothelial tumor (WDPMT) and multicystic mesothelioma. The concurrent occurrence of these entities is exceptionally uncommon and may pose challenges during surgical intervention. Both lesions are rare mesothelial proliferations that are often identified incidentally during surgery. Well differentiated papillary mesothelial tumor (WDPMT) is a neoplastic mesothelial proliferation of low malignant potential, which predominantly involves the peritoneum of young women. Microscopically it is composed of branching plump papillae lined by a single layer of bland cuboidal mesothelial cells. Cytologic atypia is minimal, and mitoses usually absent (or at most 1 mitosis per 10 high power fields). Differential diagnosis includes: 1. diffuse malignant peritoneal mesothelioma, 2. localized malignant peritoneal mesothelioma, 3. serous borderline tumors. A 41-year-old patient was admitted for laparoscopic surgery due to a tumor mass localized near the left ovary. Ultrasound examination revealed solid lesion adjacent to the left ovary, exhibiting central vascularization. The patient was diagnosed with the solid tumor mass during routine gynecological examination. The mass was extraovarian and positioned between the left ovary and the uterus. Over the course of the next 18 months, the tumor increased 5 cm in size. Given the fact that the patient presented with no symptoms, such as abdominal pain, distension or ascites, and that the tumor markers were not elevated, additional radiological imaging such as CT or MRI of the abdomen and pelvis was not performed. Intraoperatively, the mass appeared as an extraovarian solid tumor of soft consistency positioned between the left ovary and the uterus. Extirpation of the tumor was performed. Frozen section analysis of the extirpated tumor mass confirmed the diagnosis of WDPMT. During the laparoscopic procedure, a left adnexectomy was also performed and multiple biopsies of white nodules were found dispersed in the peritoneal cavity. Final patohystological analysis concluded that these nodules were peritoneal inclusion cysts. Almost three years after the procedure, the patient is without symptoms and regular clinical and ultrasound examinations were performed every six months, which showed no signs of recurrence or dissemination of the primary tumor. Recognizing well-differentiated papillary mesothelial tumor and multicystic mesothelioma is critical for accurate differential diagnosis from malignant mesothelioma. Awareness of these entities informs appropriate surgical management and follow-up protocols.