Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients.

BACKGROUND: During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D. METHODS: aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1). RESULTS: As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009). CONCLUSIONS: HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors. TRIAL REGISTRATION: NCT05735392 retrospectively registered on January 31, 2023 https://www. CLINICALTRIALS: gov/search?term=NCT05735392.

Multigenic panels in breast cancer: Clinical utility and management of patients with pathogenic variants other than BRCA1/2.

Multigene panels can analyze high and moderate/intermediate penetrance genes that predispose to breast cancer (BC), providing an opportunity to identify at-risk individuals within affected families. However, considering the complexity of different pathogenic variants and correlated clinical manifestations, a multidisciplinary team is needed to effectively manage BC. A classification of pathogenic variants included in multigene panels was presented in this narrative review to evaluate their clinical utility in BC. Clinical management was discussed for each category and focused on BC, including available evidence regarding the multidisciplinary and integrated management of patients with BC. The integration of both genetic testing and counseling is required for customized decisions in therapeutic strategies and preventative initiatives, as well as for a defined multidisciplinary approach, considering the continuous evolution of guidelines and research in the field.

Long-Term Safety of Level II Oncoplastic Surgery after Neoadjuvant Treatment for Locally Advanced Breast Cancer: A 20-Year Experience.

Background: Oncoplastic surgery (OPS) reliability in the post-neoadjuvant chemotherapy (NACT) setting is still debated due to weak scientific evidences in such scenarios. Methods: Our analysis aims to report results obtained in a retrospective series of 111 patients consecutively treated with level II OPS after NACT at the Multidisciplinary Breast Center of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS between 1998 and 2018. The surgical endpoints were the mean specimen volume, rates of positive margins (PMR), re-excision (RR), conversion to mastectomy (CMR), and complications (CR). The oncological endpoints were overall survival (OS), disease-free survival (DFS), and local recurrence (LR). To evaluate the impact of NACT on surgical and oncological outcomes at 302 months, we conducted a propensity score matching, pairing patients in post-NACT and upfront surgery groups. Results: The mean sample volume was 390,796 mm3. We registered a 3.6% of PMR, 1.8% RR, 0.9% CMR, 5% CR. The 10-year OS and 10-year DFS with a median follow-up of 88 months (6-302) were 79% and 76%, respectively, with an LR recurrence rate of 5%. The post-NACT group received significantly larger excised volumes and lower PMR. NACT did not affect surgical and oncological outcomes. Conclusions: Level II OPS can be considered a reliable alternative to mastectomy even in the post-NACT setting.

Clinical impact of drug-drug interactions on abemaciclib in the real-world experience of AB-ITALY study.

Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2- advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs' impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2- aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients' PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population's median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score <12 (15 vs 23, p = 0.005, p = 0.0017). Drug interaction was confirmed as an independent biomarker in a multivariate model (p = 0.02). No difference in any grade AE, severe toxicities, and diarrhea were detected among different age subgroups. No association was found between Drug-PIN score or Drug-PIN tier and overall toxicity (p = 0.44), severe AEs (p = 0.11), or drug reduction (p = 0.27). The efficacy and safety of abemaciclib plus ET were confirmed in a real-world setting, even in the elderly population and patients with comorbidities. Evaluation of DDIs with Drug-PIN appears to be an independent predictor of PFS.

Fatigue in patients with metastatic breast cancer undergoing single-agent taxane-based chemotherapy: a real-world data global network.

Background: Cancer-related fatigue (CRF) occurs in nearly all patients with metastatic breast cancer (MBC). Objectives: This real-world analysis aimed to describe the prevalence and importance of fatigue in patients with MBC within 3 months of treatment with single-agent taxane-based chemotherapy during the timeframe of 2020-2022 in the United States and Europe. It was also conducted to assess whether there was a difference in relapsed patients compared to patients diagnosed de novo. Design: Electronic health records were analyzed from approximately 150 million patients to identify patients with MBC who underwent taxane treatment. Results: In 2021, 50,490 patients had MBC, of whom 16,170 were diagnosed de novo and 34,330 experienced relapse. The proportion of patients undergoing taxane-based chemotherapy was 7.5% (n = 1220) and 13.4% (n = 4590), respectively, and the prevalence of any fatigue and CRF was similar between the groups (24.6% versus 25.7% and 6.6% versus 5.4%, respectively). Conclusion: At least one in four patients with MBC undergoing taxane-based treatment will experience fatigue. This highlights the importance of validating screening tools to identify CRF, which is necessary to advance clinical trials aimed at investigating treatment strategies to improve patient-centered outcomes for fatigue.

Male breast cancer: a multicenter study to provide a guide for proper management.

INTRODUCTION: To offer an extensive retrospective experience on the management of male breast cancer. METHODS: A multicenter retrospective observational cohort study was conducted, including male patients diagnosed with breast cancer (invasive or in situ) in 12 Italian breast units from January 1975 to December 2019. Patients aged 18 years or older were assessed for eligibility. Exclusion criteria were metastatic cancer at diagnosis, previous cancer(s), received neoadjuvant treatment, incomplete data on (neo) adjuvant treatment(s), and/or follow-up data. Data on radiological examinations, demographic characteristics, risk factors, histological features, receptor status, treatments, and follow-up were collected. RESULTS: In a series of 671 male patients with breast cancer assessed for eligibility, 403 (28 in situ and 375 invasive neoplasms) were included in the study. All included patients underwent surgery. The median age at surgery was 63.8 years (IQR 56.1-72.1). In 68% of cases, patients underwent echography, and in 55.1%, a mammography. Most patients were ER and PR positive (63.8%), HER2 negative (80.4%), with high (≥ 20%) Ki67 values (61.3%), and luminal B subtype (51.1%). The 10-year overall survival was 73.6% (95% CI 67.0-79.1) for invasive breast cancer and 90% (95% CI 65.6-97.4) for in situ breast cancer. In patients with invasive breast cancer, at univariable analysis, having a G3 tumor (vs. G1), pT2/3/4 (vs. pT1), pN2/3 (vs. pN0), luminal B subtype with Ki67 ≥ 20% (vs. Luminal A), were significantly associated with a higher risk of death. In multivariable analyses, pT2/3/4 (vs. pT1) remained significantly associated with a higher risk of death (HR 3.14, 95% CI 1.83-5.39), and having a HER2 positive or a triple-negative subtype (vs. Luminal A) was also significantly associated with a higher risk of mortality (HR 4.76, 95% CI 1.26-18.1). CONCLUSION: Male breast cancer is a rare disease, the better understanding of which is necessary for a more effective diagnostic and therapeutic approach.

Navigating practical challenges in immunotherapy for metastatic triple negative breast cancer.

Immunotherapy has revolutionized cancer therapy and now represents a standard of care for many tumor types, including triple-negative breast cancer. Despite the positive results that have led to the approval of immunotherapy in both early- and advanced-stage triple-negative breast cancer, pivotal clinical trials cannot address the myriad questions arising in everyday clinical practice, often falling short in delivering all the information that clinicians require. In this manuscript, we aim to address some of these practical questions, with the purpose of providing clinicians with a guide for optimizing the use of immune checkpoint inhibitors in the management of breast cancer patients and identifying opportunities for future research to clarify unresolved questions.

Sacituzumab Govitecan for the treatment of advanced triple negative breast cancer patients: a multi-center real-world analysis.

Objective: The objective of this multicenter, observational, retrospective analysis was to evaluate the safety and efficacy of sacituzumab govitecan in metastatic triple-negative breast cancer (mTNBC) patients managed according to common clinical practice in Italy. Methods: Data were retrieved by 7 sites. Triple-negative BC was defined by the lack of expression of estrogen receptor (ER <1%), progesterone receptor (PgR <1%) and human-epidermal growth factor receptor-2 (HER2 0, 1+, 2+ ISH-not amplified) according to standard ASCO-CAP criteria. Demographic and clinical characteristics were collected. Premedication, dose modifications and treatment schedule were based on the approved label of the product. Adverse events (AEs) were assessed according to NCI-CTCAE v5.0. Results: Fifty-seven eligible patients who received sacituzumab govitecan for mTNBC were included. Median age was 53 years (range 25-75). Approximately 70% of patients had an initial diagnosis of TNBC. Median time from the diagnosis of metastatic BC to start of sacituzumab govitecan was 17 months (range 0-97) and median number of previous therapies was 3 (range 1-7). The most common sites of metastasis were lymph nodes (63.1% of patients), lung (57.9%), bone (50.8%) and liver (38.6%). Eight (14.0%) patients had a disease-free interval ≤12 months. A total of 32 (56.1%) deaths were observed and the median overall survival (OS) was 12.43 months (95% CI, 7.97 months-not reached). At a median follow-up of 10.6 months, 45 patients (78.9%) had progression and the median progression-free survival (PFS) was 4.9 months (95% CI, 3.7-7.1 months). Partial tumour response was observed in 19 patients (33.3%), stable disease in 16 (28.1%) and disease progression in 22 patients (38.6%). The most common treatment-related AEs were anemia (66.6% of patients), alopecia (66.6%), neutropenia (59.6%), nausea (42.1%) and diarrhea (38.6%). Neutropenia was the most common serious treatment-related AE: 21.0% and 8.7% of patients experienced grade 3 or 4 neutropenia, respectively. Twenty-two patients (38.6%) reduced the dose and 5.3% permanently discontinued treatment. Conclusion: The results of this real-world analysis showed that both safety and efficacy of sacituzumab govitecan in mTNBC patients are consistent with that previously reported in regulatory trials. The use of premedication and supportive measures was associated with a satisfactory toxicity profile.

Preventing Bone Loss in Breast Cancer Patients: Designing a Personalized Clinical Pathway in a Large-Volume Research Hospital.

BACKGROUND: We assess the impact of bone health clinical management in breast cancer (BC) patients receiving adjuvant endocrine therapy and design a personalized clinical pathway to reduce bone loss in an Italian research hospital. METHODS: The primary endpoint was to assess (through the process improvement organizational method) the clinical pathway that post-surgical BC patients prescribed with endocrine therapy undergo to prevent bone loss. The secondary endpoint was to design a personalized clinical pathway for a prompt implementation of guidelines, to assess and possibly prescribe antiresorptive therapy. RESULTS: During the first year of the execution of the new Diagnostic Therapeutic Assistance Pathway, a 60% increase in Dual-Energy X-ray Absorptiometry evaluations within 30 days and a 39.5% increase in antiresorptive therapy prescription within 90 days (since the prescription of endocrine therapy) were shown, thus increasing patients' compliance. CONCLUSION: Case managers and bone health specialists in this context can improve patients' adherence to therapies and bone health, helping physicians to expand their collaboration.

Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella and Mammella Intergruppo trials.

Background: Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall survival (OS) in adjuvant breast cancer trials. Methods: Individual patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each ICE at both the outcome (i.e., OS and ICE are correlated irrespective of treatment) and trial (i.e., treatment effects on ICE and treatment effect on OS are correlated) levels. The following ICEs were considered as potential surrogate endpoints of OS: disease-free survival (DFS), distant disease-free survival (DDFS), distant relapse-free survival (DRFS), recurrence-free survival (RFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and invasive breast cancer-free survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted linear regression. Kendall's τ and R2 ≥ 0.70 were considered as indicators of a clinically relevant surrogacy. Findings: Among the 12,397 patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49-65). After a median follow-up of 10.3 years (IQR 6.4-14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year ICE. At the trial-level, treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI. Interpretation: Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in breast cancer adjuvant trials. Funding: This analysis was supported by the Italian Association for Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of Health-5 × 1000 funds (years 2021-2022).

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.

Bridging gaps in cancer cachexia Care: Current insights and future perspectives.

Cachexia is characterized by severe weight loss and skeletal muscle depletion, and is a threat to cancer patients by worsening their prognosis. International guidelines set indications for the screening and diagnosis of cancer cachexia and suggest interventions (nutritional support, physical exercise, and pharmacological treatments). Nevertheless, real-life experience not always aligns with such indications. We aimed to review the current state of the field and the main advancements, with a focus on real-life clinical practice from the perspectives of oncologists, nutrition professionals, and radiologists. Pragmatic solutions are proposed to improve the current management of the disease, emphasizing the importance of increasing awareness of clinical nutrition's benefits, fostering multidisciplinary collaboration, promoting early identification of at-risk patients, and leveraging available resources. Given the distinct needs of patients who are receiving oncologic anti-cancer treatments and those in the follow-up phase, the use of tailored approaches is encouraged. The pivotal role of healthcare professionals in managing patients in active treatment is highlighted, while patient and caregiver empowerment should be strengthened in the follow-up phase. Telemedicine and web-based applications represent valuable tools for continuous monitoring of patients, facilitating timely and personalized intervention through effective communication between patients and healthcare providers. These actions can potentially improve the outcomes, well-being, and survival of cancer patients with cachexia.

An Integrated Care Approach to Improve Well-Being in Breast Cancer Patients.

BACKGROUND: Breast cancer (BC) treatment has recently been revolutionized by the introduction of newer targeted agents, that helped tailoring therapies around the single patient. Along with increased survival rates, a careful evaluation of diet, lifestyle habits, physical activity, emotional and psychological experiences linked to the treatment journey, is now mandatory. However, a true proposal for an omnicomprehensive and "integrative" approach is still lacking in literature. METHODS: A scientific board of internationally recognized specialists throughout different disciplines designed a shared proposal of holistic approach for BC patients. RESULTS: A narrative review, containing information on BC treatment, endocrinological and diet aspects, physical activity, rehabilitation, integrative medicine, and digital narrative medicine, was developed. CONCLUSIONS: In the context of a patient-centered care, BC treatment cannot be separated from a patient's long-term follow-up and care, and an organized interdisciplinary collaboration is the future in this disease's cure, to make sure that our patients will live longer and better. TRIAL REGISTRATION: NCT05893368: New Model for Integrating Person-based Care (PbC) in the Treatment of Advanced HER2-negative Breast Cancer (PERGIQUAL). Registration date: 29th May 2023.

Breaking barriers in triple negative breast cancer (TNBC) - Unleashing the power of antibody-drug conjugates (ADCs).

Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen, conjugated to a cytotoxic agent through a cleavable or non-cleavable synthetic linker. The rationale behind the development of ADCs is to overcome the limitations of conventional chemotherapy, such as the narrow therapeutic window and the emergence of resistance mechanisms. ADCs had already revolutionized the treatment algorithm of HER2-positive breast cancer. Currently, emergent non-HER2 targeted ADCs are gaining momentum, with special focus on triple-negative disease therapeutic landscape. Sacituzumab govitecan (SG) is an ADC consisting of a humanized monoclonal antibody hRS7 targeting trophoblast cell surface antigen 2 (Trop2), linked to the topoisomerase I inhibitor SN-38 by a hydrolysable linker. It currently stands as the only non-HER2 targeted ADC that already received approval for the treatment of unresectable locally advanced or metastatic triple negative breast cancer (TNBC) in patients who had received two or more prior systemic therapies, with at least one for advanced disease. The purpose of these review is to analyze the available evidence regarding ADCs in TNBC, alongside with providing an overview on the ongoing and future research horizons in this field.