DNA damage targeted therapy for advanced breast cancer.

Breast cancer (BC) is the most prevalent malignancy affecting women worldwide, including Portugal. While the majority of BC cases are sporadic, hereditary forms account for 5-10% of cases. The most common inherited mutations associated with BC are germline mutations in the BReast CAncer (BRCA) 1/2 gene (gBRCA1/2). They are found in approximately 5-6% of BC patients and are inherited in an autosomal dominant manner, primarily affecting younger women. Pathogenic variants within BRCA1/2 genes elevate the risk of both breast and ovarian cancers and give rise to distinct clinical phenotypes. BRCA proteins play a key role in maintaining genome integrity by facilitating the repair of double-strand breaks through the homologous recombination (HR) pathway. Therefore, any mutation that impairs the function of BRCA proteins can result in the accumulation of DNA damage, genomic instability, and potentially contribute to cancer development and progression. Testing for gBRCA1/2 status is relevant for treatment planning, as it can provide insights into the likely response to therapy involving platinum-based chemotherapy and poly[adenosine diphosphate (ADP)-ribose] polymerase inhibitors (PARPi). The aim of this review was to investigate the impact of HR deficiency in BC, focusing on BRCA mutations and their impact on the modulation of responses to platinum and PARPi therapy, and to share the experience of Unidade Local de Saúde Santa Maria in the management of metastatic BC patients with DNA damage targeted therapy, including those with the Portuguese c.156_157insAlu BRCA2 founder mutation.

Effect of Cyclin-Dependent Kinase 4/6 Inhibitors on Circulating Cells in Patients with Metastatic Breast Cancer.

The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard-of-care for estrogen receptor (ER)-positive, HER2-negative (ER+/HER2- advanced/metastatic breast cancer (mBC). However, the impact of CDK4/6i on circulating immune cells and circulating tumor cells (CTCs) in patients receiving CDK4/6i and ET (CDK4/6i+ET) remains poorly understood. This was a prospective cohort study including 44 patients with ER+/HER2- mBC treated with CDK4/6i+ET in either first or second line. Peripheral blood samples were collected before (baseline) and 3 months (t2) after therapy. Immune cell's subsets were quantified by flow cytometry, and microfluidic-captured CTCs were counted and classified according to the expression of cytokeratin and/or vimentin. Patients were categorized according to response as responders (progression-free survival [PFS] ≥ 6.0 months; 79.1%) and non-responders (PFS < 6.0 months; 20.9%). CDK4/6i+ET resulted in significant changes in the hematological parameters, including decreased hemoglobin levels and increased mean corpuscular volume, as well as reductions in neutrophil, eosinophil, and basophil counts. Specific immune cell subsets, such as early-stage myeloid-derived suppressor cells, central memory CD4+ T cells, and Vδ2+ T cells expressing NKG2D, decreased 3 months after CDK4/6i+ET. Additionally, correlations between the presence of CTCs and immune cell populations were observed, highlighting the interplay between immune dysfunction and tumor dissemination. This study provides insights into the immunomodulatory effects of CDK4/6i+ET, underscoring the importance of considering immune dynamics in the management of ER+/HER2- mBC.

Breast Sarcomas, Phyllodes Tumors, and Desmoid Tumors: Turning the Magnifying Glass on Rare and Aggressive Entities.

Breast sarcomas (BSs), phyllodes tumors (PTs), and desmoid tumors (DTs) are rare entities that arise from connective tissue. BSs can be classified as either primary or secondary, whether they develop de novo or after radiation exposure or lymphedema. PIK3CA seems to play an important common role in different BS. Malignant PTs show similar behavior to BSs, while DTs are locally aggressive but rarely metastasize. BSs usually present as unilateral, painless, rapidly growing masses with rare nodal involvement. The diagnosis should be based on magnetic resonance imaging and a core needle biopsy. Staging should comprise a chest computed tomography (CT) scan (except for benign PT and DT), while abdominal and pelvic CT scans and bone scans should be added in certain subtypes. The mainstay of treatment for localized BS is surgery, with margin goals that vary according to subtype. Radiotherapy and chemotherapy can be used as neoadjuvant or adjuvant approaches, but their use in these settings is not standard. Advanced BS should be treated with systemic therapy, consistent with recommendations for advanced soft tissue sarcomas of other topographies. Given the rarity and heterogeneity of these entities, multidisciplinary and multi-institutional collaboration and treatment at reference centers are critical.

Non-endometrioid endometrial cancer: Analysis of different adjuvant treatment modalities.

BACKGROUND: Adjuvant treatment for endometrial carcinoma (EC) is decided based on risk assessment. Tumors of non-endometrioid (NE) histology are classified as high-risk and adjuvant treatment is recommended. MATERIALS AND METHODS: We analyzed retrospectively all NEEC patients treated in two Portuguese oncology centers, between 2009 and 2018. Comparison of adjuvant modalities were performed by overall survival (OS) and disease-free survival (DFS) analysis. RESULTS: A total of 66 patients were included, with mean age 69 years. Serous histology was found in 34 patients (51.5%), clear-cell in 13 (19.7%) and carcinosarcoma in 18 (27.3%). Based on FIGO staging-system, 34 (51.5%) patients were diagnosed at stages III-IV. Following surgery, no further treatment was performed in 16 patients (24.4%), 11 (16.7%) received isolated chemotherapy (CT), 11 (16.7%) isolated radiotherapy (RT) and 28 (42.4%) combination therapy (CT+RT). Kaplan-Meier analysis showed higher median (m)DFS in the CT+RT group: 30.7 months (m) compared to RT alone: 14.1 m. The mDFS of the isolated CT group was 10.8 m and for patients with no further treatment it was 5.7 m, p = 0.03. Median OS was also increased in the combination group CT+RT (78.3 m) compared to isolated RT (64.3 m), isolated CT (37.3 m) and no further treatment (46.7 m), p=0.005. Multivariate Cox-regression using CT+RT as reference, showed hazard-ratio of 3.5 (p = 0.05) and 4.5 (p = 0.01) for the CT and for no-treatment group respectively. CONCLUSIONS: In NEEC patients, DFS and OS analysis showed better prognosis in combination of CT+RT. Patients that underwent only RT had better survival outcomes when compared to those treated with CT only.