The emerging predictive and prognostic role of HER2 in HER2-negative early breast cancer: a retrospective study.

PURPOSE: Many patients with early breast cancer (eBC) undergoing neoadjuvant chemotherapy do not achieve pathological complete response (pCR), which is a prognostic factor. We examined the role of HER2-low expression in predicting pCR and prognosis in HER2-negative eBC. METHODS: We evaluated patients with stage I-III HER2-negative BC, treated between 2013 and 2023 at The Royal Marsden NHS Foundation Trust, London. Tumors were classified based on estrogen receptor (ER) status and into HER2-low and HER2-zero subgroups. We analyzed pCR rates, relapse-free survival (RFS) and overall survival (OS). RESULTS: 754 patients were included in the analysis. pCR rate was 8.9% in the ER+ /HER2-low, 16.5% in the ER+ /HER2-zero, 38.9% in the ER- ER-/HER2-low and 35.9% in the ER-/HER2-zero eBC (p < 0.001). Multivariable analysis showed a significantly lower pCR rate in HER2-low compared to HER2-zero BC in the ER+ subgroup. At a median follow-up of 63.8 months (59.9-67.4), we observed longer OS in HER2-low compared to HER2-zero patients in the overall and in the ER+ population. There was no predictive or prognostic impact of HER2-low status in the ER- population. CONCLUSION: This study supports the interpretation of HER2 status as a possible prognostic and predictive biomarker for HER2-negative eBC, especially among patients with ER+ disease.

Hormone Receptor-Positive/HER2-Positive Breast Cancer: Hormone Therapy and Anti-HER2 Treatment: An Update on Treatment Strategies.

Hormone receptor (HR)-positive/HER2-positive breast cancer represents a distinct subtype expressing estrogen and progesterone receptors with an overexpression of HER2. Approximately 14% of female breast cancer cases are HER2-positive, with the majority being HR-positive. These tumors show a cross-talk between the hormonal and HER2 pathways; the interaction has implications for the treatment options for the disease. In this review, we analyze the biology of HR-positive/HER2-positive breast cancer and summarize the evidence concerning the standard of care options both in neoadjuvant/adjuvant settings and in advanced disease. Additionally, we focus on new trials and drugs for HR-positive/HER2-positive breast cancer and the new entity: HER2-low breast cancer.

Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing.

Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer.

Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer-Immun-HER trial (GOIRC-01-2016).

BACKGROUND: It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab. METHODS: In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD). RESULTS: Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms. CONCLUSIONS: SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response. TRIAL REGISTRATION NUMBER: NCT03144947, and EudraCT number: 2016-000435-41.

RAD51 as a biomarker for homologous recombination deficiency in high-grade serous ovarian carcinoma: robustness and interobserver variability of the RAD51 test.

The RAD51 test is emerging as a promising biomarker for the assessment of functional homologous recombination deficiency (HRD). Yet, the robustness and reproducibility of the immunofluorescence-based RAD51 test, in different academic laboratories, have not been systematically investigated. Therefore, we tested the performance of the RAD51 assay in formalin-fixed paraffin-embedded (FFPE) high-grade serous ovarian carcinoma (HGSOC) samples in four European laboratories. Here, we confirm that subtle differences in staining procedures result in low variability of RAD51 and γH2AX scores. However, substantial variability in RAD51 scoring was observed in some samples, likely due to complicating technical and biological features, such as high RAD51 signal-to-noise ratio and RAD51 heterogeneity. These results support the need to identify and perform additional quality control steps and/or automating image analysis. Altogether, resolving technical issues should be a priority, as identifying tumours with functional HRD is urgently needed to guide the individual treatment of HGSOC patients. Follow-up studies are needed to define the key tissue quality requirements to assess HRD by RAD51 in FFPE tumour samples, as this test could help in guiding the individual treatment of HGSOC patients.

BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors.

Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as "benign." However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer. SIGNIFICANCE: PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.

Long-Term Effects of Breast Cancer Therapy and Care: Calm after the Storm?

Breast cancer is still a lethal disease and the leading cause of death in women, undermining patients' survival and quality of life. Modern techniques of surgery and radiotherapy allow for the obtaining of good results in terms of survival, however they cause long-term side effects that persist over time, such as lymphedema and neuropathy. Similarly, the advent of new therapies such as endocrine therapy revolutionized breast cancer outcomes, but side effects are still present even in years of follow-up after cure. Besides the side effects of medical and surgical therapy, breast cancer is a real disruption in patients' lives considering quality of life-related aspects such as the distortion of body image, the psychological consequences of the diagnosis, and the impact on family dynamics. Therefore, the doctor-patient relationship is central to providing the best support both during treatment and afterwards. The aim of this review is to summarize the consequences of medical and surgical treatment on breast cancer patients and to emphasize the importance of early prevention of side effects to improve patients' quality of life.

HER2-Low Status Does Not Affect Survival Outcomes of Patients with Metastatic Breast Cancer (MBC) Undergoing First-Line Treatment with Endocrine Therapy plus Palbociclib: Results of a Multicenter, Retrospective Cohort Study.

BACKGROUND: Approximately 45-50% of breast cancers (BCs) have a HER2 immunohistochemical score of 1+ or 2+ with negative in situ hybridization, defining the "HER2-low BC" subtype. No anti-HER2 agents are currently approved for this subgroup in Europe, where treatment is still determined by HR expression status. In this study, we investigated the prognostic significance of HER2-low status in HR+/HER2- metastatic BC (MBC) patients treated with endocrine therapy (ET) plus palbociclib as first line. METHODS: We conducted a retrospective study including 252 consecutive HR+/HER2- MBC patients who received first-line ET plus palbociclib at six Italian Oncology Units between March 2016 and June 2021. The chi-square test was used to assess differences in the distribution of clinical and pathological variables between the HER-0 and HER2-low subgroups. Survival outcomes, progression-free survival (PFS) and overall survival (OS), were calculated by the Kaplan-Meier method, and the log-rank test was performed to estimate the differences between the curves. RESULTS: A total of 165 patients were included in the analysis: 94 (57%) and 71 (43%) patients had HER2-0 and HER2-low disease, respectively. The median age at treatment start was 64 years. No correlation between patients and tumor characteristics and HER2 status was found. Median PFS (mPFS) for the entire study cohort was 20 months (95% CI,18-25 months), while median OS (mOS) was not reached at the time of analysis. No statistically significant differences, in terms of PFS (p = 0.20) and OS (p = 0.1), were observed between HER2-low and HER2-0 subgroups. CONCLUSIONS: In our analysis, HR+ MBC patients with low HER2 expression who received first-line treatment with ET plus Palbociclib reported no statistically different survival outcomes compared to HER2-0 patients. Further prospective studies are needed to confirm the clinical role of HER2 expression level.

The Innate Immune Microenvironment in Metastatic Breast Cancer.

The immune system plays a fundamental role in neoplastic disease. In the era of immunotherapy, the adaptive immune response has been in the spotlight whereas the role of innate immunity in cancer development and progression is less known. The tumor microenvironment influences the terminal differentiation of innate immune cells, which can explicate their pro-tumor or anti-tumor effect. Different cells are able to recognize and eliminate no self and tumor cells: macrophages, natural killer cells, monocytes, dendritic cells, and neutrophils are, together with the elements of the complement system, the principal players of innate immunity in cancer development and evolution. Metastatic breast cancer is a heterogeneous disease from the stromal, immune, and biological point of view and requires deepened exploration to understand different patient outcomes. In this review, we summarize the evidence about the role of innate immunity in breast cancer metastatic sites and the potential targets for optimizing the innate response as a novel treatment opportunity.

Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification.

PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies. SIGNIFICANCE: This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin.

A narrative review of the principal glucocorticoids employed in cancer.

Glucocorticoids (GCs) are a pharmacological class of drugs widely used in oncology in both supportive and palliative settings. GCs differentially impact organs with immediate and long-term effects; with suppressive effect on the immune system anchoring their use to manage the toxicities of immune checkpoint inhibitors (ICIs). In addition, GCs are often used in the management of symptoms related to cancer or chemotherapy and as adjuvants in the treatment of pain in the management of other. In the palliative setting, GCs, especially administered subcutaneously can be to assist in the control of nausea, dyspnea, asthenia, and anorexia-cachexia syndrome. In this narrative review, we aim to summarize the role of GCs in the different settings (curative, supportive, and palliative) to help clinicians use these important drugs in their daily clinical practice with cancer patients.

A review of immune checkpoint blockade in breast cancer.

In the recent years characterized by the cancer immunotherapy revolution, attention has turned to how to potentially boost and/or generate an efficient anti-tumor immune response in breast cancer (BC). Clinical activity of immune checkpoint blockade (ICB) targeting PD-1 or PD-L1 in BC has been more evident in the triple negative subtype and in earlier lines of the treatment. Remarkably, some responders to single agent ICB have achieved durable responses with metastatic disease, possibly as a result of treatment-induced immunological memory. However, most BC are immunologically quiescent and current research efforts developing ICB combinations are attempting to convert "cold" into "hot" tumors by manipulating the tumor microenvironment, expanding anti-tumor T cells improving efficient antigen presentation, and suppressing pro-tumor inhibitory cells. The aim of this review is to summarize existing data on the efficacy of immune checkpoint blockers as single agents and combination strategies in all BC subtypes, highlighting the BC subgroups that benefit most from ICB.

Biological Role and Clinical Implications of microRNAs in BRCA Mutation Carriers.

Women with pathogenic germline mutations in BRCA1 and BRCA2 genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual's genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression. MiRNAs are dysregulated at all stages of breast cancer and although they are accessible and evaluable, a standardized method for miRNA assessment is needed to ensure comparable data analysis and accuracy of results. The aim of this review was to highlight the role of miRNAs as potential biological markers for BRCA mutation carriers. In particular, biological and clinical implications of a link between lifestyle and nutritional modifiable factors, miRNA expression and germline BRCA1 and BRCA2 mutations are discussed with the knowledge of the best available scientific evidence.

Luminal Breast Cancer: Risk of Recurrence and Tumor-Associated Immune Suppression.

Hormone-receptor positive (HR+) breast cancer (BC) (including the luminal A and the luminal B subtypes) is the most common type of tumor in women diagnosed with early-stage BC (EBC). It represents a highly heterogeneous subgroup that is characterized by different risks of relapse. The aim of this review is to discuss the possible role played by the immune response in predicting this risk, along with the most common clinical and pathological factors and molecular tools that have been developed and are already in use. As opposed to what has previously been observed in the most aggressive human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC) subtypes, a high proportion of tumor-infiltrating lymphocytes (TILs)-reflecting a spontaneous and pre-existing immune response to the tumor-has been linked to a worse prognosis in HR+ EBC. This work provides some immune biological rationale explaining these findings and provides the basics to understand the principal clinical trials that are testing immunotherapy in HR+ (luminal) BC.

Current overview and special considerations for second breast cancer in Hodgkin lymphoma survivors.

Second breast cancer (SBC) is the most common solid cancer among Hodgkin Lymphoma (HL) female survivors. We reviewed the related modifying risk factors, radiation-induced carcinogenesis, tumors characteristics, management specificities, prevention and surveillance modalities based on current evidence. The risk of developing SBC may be influenced essentially by the age at HL treatment, follow-up latency, dose of irradiation received and the extent of irradiated field. SBCs generally develop at younger age, they are often bilateral, and exhibit more aggressive biological features and worse prognosis. No firm answer about the benefits of breast surveillance is provided by literature, but compelling evidence tends toward a clinical benefit in early detection. Increasing awareness among health providers' care and current survivors as well as the implementation of screening measures is crucial. Great efforts are ongoing in individualizing treatment strategies for future HL patients and response-adapted approaches are holding promise in prevention of these second malignancies.

Clinico-Immunological Profile of a 67-Year-Old Woman Affected by HER2-Positive Breast Cancer and Autoimmune Dermatomyositis.

A patient with HER2-positive early breast cancer (BC) developed dermatomyositis (DM), which disappeared after the first administration of adjuvant trastuzumab. No HER2 overexpression/amplification was observed in DM skin biopsies. Both BC and skin immune infiltrates were composed mostly of CD3+ T-lymphocytes. Interestingly, tumor-infiltrating lymphocytes expressed PD-1, which was negligible in skin-infiltrating lymphocytes, while both BC cells and keratinocytes were PD-L1-positive. High serum levels of endogenous anti-HER2 antibodies were detected, confirming the induction of a HER2-specific adaptive immune response. It may be argued that HER2-specific T-lymphocytes cross-reacted with one or more unknown skin antigens, causing DM. Trastuzumab may have silenced skin cross-reaction by eliminating any residual HER2-positive micrometastatic disease and, thus, inducing DM remission.

Role of innate and adaptive immunity in the efficacy of anti-HER2 monoclonal antibodies for HER2-positive breast cancer.

Anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab are effective for all stages of HER2-positive breast cancer (BC). However, intrinsic or acquired resistance to these drugs may occur in a significant number of patients (pts) and, except for HER2 status, no validated predictive factors of response/resistance have been identified to date. This lack is in part due to the not yet fully elucidated mechanism of action of mAbs in vivo. Increasing evidence suggests a significant contribution of both innate and adaptive immunity to the antitumor effects of mAbs. The aim of this review was to describe the role of innate and adaptive immunity in the efficacy of anti-HER2 mAbs and to report known and novel strategies to be used for optimizing immune effects of anti-HER2 therapies for HER2-positive BC.

Oncologist Burnout Syndrome in Eastern Europe: Results of the Multinational Survey.

PURPOSE: Burnout is defined as a three-dimensional syndrome-emotional exhaustion (EE), depersonalization (DP), and reduced personal accomplishment (PA)-caused by chronic occupational stress. The aim of the current study was to investigate the prevalence of burnout among oncologists in Eastern Europe and to identify the contributing factors. METHODS: The study was conducted as an online survey between October 2017 and March 2018. Oncologists (including medical, radiation, clinical, and surgical oncologists) from 19 countries were invited to participate. The survey consisted of 30 questions, including the standardized burnout instrument, Maslach Burnout Inventory, and eight demographic questions. Burnout risk was scored according to the scoring manual for health care workers. RESULTS: The study included 637 oncologists. Overall, 28% were at low or intermediate risk and 72% were at high risk for burnout. Forty-four percent of participants were at high risk for EE, 28.7% for DP, and 47.3% for PA. EE risk was associated with female sex. DP risk was highest among clinical and radiation oncologists, whereas PA risk was positively correlated with years of service, percentage of cancer deaths, and availability of the number of oncologists. In multivariate logistic regression analysis, burnout was significantly associated with standardized cancer mortality and fewer years of practice. CONCLUSION: Burnout among oncologists in Eastern Europe is high, and younger oncologists are the most vulnerable group. Preventive measures should be taken to address this issue, which negatively affects optimal care delivery and poses a threat to oncologists' health and well-being.