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Pre-surgical treatments in patients with early breast cancer allows a direct estimation of treatment efficacy, by comparing the tumor and the treatment. Patients who achieve a pathological complete response at surgery have a better prognosis, with lower risk of disease recurrence and death. Hence, clinical research efforts have been focusing on high-risk patients with residual disease at surgery, who may be “salvaged” through additional treatments administered in the post-neoadjuvant setting. In the present review, we aim to illustrate the development and advantages of the post-neoadjuvant setting, and to discuss the available strategies for patients with early breast cancer, either approved or under investigation. This review was written after literature search on main scientific databases (e.g. PubMed) and conference proceedings from major oncology conferences up to 1 August 2022. T-DM1 and capecitabine are currently approved as post-neoadjuvant treatments for patients with HER2-positive and triple-negative breast cancer, respectively, with residual disease at surgery. More recently, other treatment strategies have been approved for patients with high-risk early breast cancer, including the immune checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib and the CDK 4/6 inhibitor abemaciclib. Novel agents and treatment combinations are currently under investigation as promising post-neoadjuvant treatment strategies., SCOPUS: re.j, info:eu-repo/semantics/published

Introduction: Triple negative breast cancer (TNBC) is an area of high unmet medical need in terms of new effective treatment strategies. Although breast cancer is traditionally considered a ‘cold’ tumor type, TNBC is the most appropriate subtype for immunotherapeutic strategies; this is due to the high level of tumor infiltrating lymphocytes, PD-L1 expression, and tumor mutational burden compared to other breast cancer subtypes. Areas covered: This review examines the available evidence on the use of immunotherapeutic strategies in early and advanced TNBC, discusses the pitfalls and limitations often encountered in clinical research, and summarizes data on novel promising immunomodulatory approaches that have been explored in early-phase trials. Expert opinion: PD-1-blockade is approved for stage II/III TNBC and for first-line treatment of PD-L1-positive TNBC patients with metastatic disease and should be considered standard of care. However, question marks and difficulties remain; these include the identification of predictive biomarkers to select patients who benefit from the addition of PD1-blockade and the balance between efficacy and long-term toxicity for an individual patient. Numerous treatment combinations and new immunotherapeutic strategies beyond PD1 blockade are being evaluated, thus reflecting a promising evolution towards a more personalized approach, and extended clinical benefit in TNBC. Abbreviations:Triple-negative breast cancer (TNBC); breast cancers (BCs); estrogen receptor (ER); progesterone receptor (PgR); human epidermal growth factor-2 (HER-2); basal-like 1 (BL1), basal-like 2 (BL2); mesenchymal (MES); mesenchymal stem-like (MSL); immunomodulatory (IM); luminal androgen receptor (LAR); basal-like immunosuppressed (BLIS); basal-like immune-activated (BLIA); tumor-infiltrating lymphocytes (TILs); tumor mutational burden (TMB); immune cells (ICs); immunohistochemistry (IHC); overall response rate (ORR); overall survival (OS); progression-free s, SCOPUS: re.j, info:eu-repo/semantics/published

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Patients with breast cancer undergoing systemic therapies can have mixed response to treatment, with some lesions reducing their dimensions or also, in some cases, disappearing, and others progressing. Of note, breast cancer is an example of tumor heterogeneity, and this reflects the ability of the tumor to adapt to changing conditions and to overcome constraints to growth and dissemination. Hence, a mixed response to treatment may indicate that some clones have become resistant to the treatment and are triggering a disease progression. Nevertheless, a differential diagnosis should always be implemented when new lesions are detected, to rule out potential different etiologies. Too often subjects who received a prior diagnosis of cancer may face stigma of “cancer patients” although they have been successfully cured and have no evidence of residual disease. The systematic implementation of a sensible, appropriate differential diagnosis can help reduce the time to diagnosis and to treatment, with positive impact in patients’ outcomes and quality of life. Our case report describes the incidental finding of lung lesions in a woman treated for early breast cancer and highlights the importance of differential diagnosis in the specific subset of subjects who received a prior diagnosis of cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

In early-stage HER2-positive breast cancer, biomarkers that guide deescalation and/or escalation of systemic therapy are needed. CelTIL score is a novel, combined biomarker based on stromal tumor-infiltrating lymphocytes and tumor cellularity and is determined in tumor biopsies at week 2 of anti-HER2 therapy only. We evaluated the prognostic value of CelTIL in 196 patients with early-stage HER2-positive disease treated with standard trastuzumab-based chemotherapy in the NeoALTTO phase III trial. Using a prespecified CelTIL cutoff, a better 5-year event-free survival and overall survival was observed between CelTIL-high and CelTIL-low score with a 76.4% (95% confidence interval [CI] = 68.0% to 85.0%) vs 59.7% (95% CI = 50.0% to 72.0%) (hazard ratio = 0.40, 95% CI = 0.17 to 0.94) and 86.4% (95% CI = 80.0% to 94.0%) vs 73.5% (95% CI = 64.0% to 84.0%) (hazard ratio = 0.43, 95% CI = 0.20 to 0.92), respectively. Statistical significance was maintained after adjusting for baseline tumor-infiltrating lymphocytes, hormone receptor status, pretreatment tumor size and nodal status, type of surgery, treatment arm, and pathological complete response. Further studies to support CelTIL as an early readout biomarker to help deescalate or escalate systemic therapy in HER2-positive breast cancer seem warranted., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

It has been suggested that the benefit of adjuvant chemotherapy (CT) in premenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) early breast cancer may be related, at least in part, to CT-induced ovarian function suppression (OFS) in this subgroup of patients. Although this hypothesis has not been directly tested in large randomized clinical trials, the observations from prospective studies have been remarkably consistent in showing a late benefit of CT among the subgroup of patients who benefit (ie, women who were close to menopause). The hypothesis has important clinical implications, as it may be possible to spare the associated adverse effects of adjuvant CT in a select group of women with early breast cancer, in favor of optimizing OFS and endocrine therapy (ET), without compromising clinical outcomes. Such an approach has the added benefit of preserving the key quality of life outcomes in premenopausal women, particularly by preventing the irreversible loss of ovarian function that may result from CT use. For this reason, we convened an international panel of clinical experts in breast cancer treatment to discuss the key aspects of the available data in this area, as well as the potential clinical implications for patients. This article summarizes the results of these discussions and presents the consensus opinion of the panel regarding optimizing the use of OFS for premenopausal women with HR+, HER2- early breast cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Young age at breast cancer (BC) diagnosis has historically been a rationale for overtreatment. Limited data with short follow-up exist on the prognostic value of age at diagnosis in HER2-positive BC and the benefit of anti-HER2 therapy in young patients. Methods: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in HER2-positive early BC patients investigating the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab. The prognostic and predictive value of age on invasive disease-free survival (IDFS) as continuous and dichotomous variable (aged 40 years or younger and older than 40 years) was assessed. A subpopulation treatment effect pattern plot analysis was conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor. Results: Of 4804 included patients, 768 (16.0%) were aged 40 years or younger at enrollment. Median follow-up was 74 (interquartile range = 62-75) months. Young age was not prognostic either as dichotomous (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.84 to 1.33) or continuous (HR = 1.00, 95% CI = 1.00 to 1.01) variable. Lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No statistically significant interaction was observed between age and pertuzumab effect (Pinteraction = 0.61). Adding pertuzumab improved IDFS for patients in the young (HR = 0.86, 95% CI = 0.56 to 1.32) and older (HR = 0.75, 95% CI = 0.62 to 0.92) cohorts. Similar results were observed irrespective of hormone receptor status. Subpopulation treatment effect pattern plot analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations. Conclusions: In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate either prognostic or predictive value, irrespective of hormone receptor status., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Solid cancer is an independent prognostic factor for poor outcome with COVID-19. As guidelines for patient management in that setting depend on retrospective efforts, we here present the first analyses of a nationwide database of patients with cancer hospitalized with COVID-19 in Belgium, with a focus on changes in anticancer treatment plans at the time of SARS-CoV-2 infection. Methods: Nineteen Belgian hospitals identified all patients with a history of solid cancer hospitalized with COVID-19 between March 2020 and February 2021. Demographic, cancer-specific and COVID-specific data were pseudonymously entered into a central Belgian Society of Medical Oncology (BSMO)-COVID database. The association between survival and primary cancer type was analyzed through multivariate multinomial logistic regression. Group comparisons for categorical variables were carried out through a Chi-square test. Results: A total of 928 patients were registered in the database; most of them were aged ≥70 years (61.0%) and with poor performance scores [57.2% Eastern Cooperative Oncology Group (ECOG) ≥2]. Thirty-day COVID-related mortality was 19.8%. In multivariate analysis, a trend was seen for higher mortality in patients with lung cancer (27.6% versus 20.8%, P = 0.062) and lower mortality for patients with breast cancer (13.0% versus 23.3%, P = 0.052) compared with other tumour types. Non-curative treatment was associated with higher 30-day COVID-related mortality rates compared with curative or no active treatment (25.8% versus 14.3% versus 21.9%, respectively, P < 0.001). In 33% of patients under active treatment, the therapeutic plan was changed due to COVID-19 diagnosis, most frequently involving delays/interruptions in systemic treatments (18.6%). Thirty-day COVID-related mortality was not significantly different between patients with and without treatment modifications (21.4% versus 20.5%). Conclusion: Interruption in anticancer treatments at the time of SARS-CoV-2 inf, SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage HER2-positive breast cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models. Methods: Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival in 180 patients enrolled in the phase III trial Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO), which randomly assigned stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pretreatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase II trial NeoSphere. Results: In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse event-free survival in patients treated with trastuzumab-based therapy (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.20 to 2.46), but not with lapatinib-based (HR = 1.02, 95% CI = 0.68 to 1.53) or trastuzumab-lapatinib-based (HR = 1.08, 95% CI = 0.60 to 1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient disease-free survival in both the whole study cohort (HR = 1.197, 95% CI = 1.002 to 1.428) and patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI = 1.049 to 1.568). Conclusions: High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Geographic location and national income may influence access to innovation in healthcare. We aimed to study if geographical location and national income influenced the timelines to activate the global phase III APHINITY trial, evaluating adjuvant pertuzumab in patients with HER2-positive early breast cancer. Methods: Time from regulatory authority (RA) submission to approval (RAA), time to Ethics Committee/Institutional Review Board (EC/IRB) approval, time from study approval by EC/IRB to first randomised patient and from first to last randomised patient were collected. Analyses were conducted grouping countries by geographical region or economic income classification. Results: Forty-one countries (of 42) had data available regarding all relevant timelines. No statistical difference was observed between the time to RAA and geographical region (p = 0.47), although there was a trend to longer time to RAA in upper middle-income economies (p = 0.07). Except for time from first to last patient randomised, there was wide variation in timelines overall and within geographical regions and economic income groups. Conclusions: Geographical location and income classification did not appear to be the major drivers influencing time for clinical trial activation. Wide variability in activation timelines within geographical regions and income groups exists and is worthy of further investigation., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Brain metastases (BMs) are frequent events in patients with HER2-positive metastatic breast cancer (MBC) and are associated with poor prognosis. Small-molecule anti-HER2 tyrosine kinase inhibitors (TKIs) are promising agents for the treatment of BM. In this study, we assess the clinical outcomes of patients with HER2-positive MBC and BM treated with TKI-containing regimens compared with those treated with non-TKI-containing regimens. Materials and methods: PubMed, Embase, Cochrane Library, and conference proceedings (ASCO, SABCS, ESMO, and ESMO Breast) were searched up to June 2021. The primary endpoint was progression-free survival (PFS) in patients with BM. Secondary endpoints included PFS in patients without BM and overall survival (OS). The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Overall effects were pooled using random-effects models. Results: This systematic review and meta-analysis included data from 2437 patients (490 with and 1947 without BM at baseline) enrolled in five trials assessing tucatinib-, lapatinib-, pyrotinib-, or afatinib-based combinations. A nonstatistically significant PFS benefit favoring TKI-containing regimens was observed in both patients with BM [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.41-1.12; P = 0.13] and without BM (HR 0.55, 95% CI 0.24-1.26; P = 0.16). Sensitivity analysis, excluding each study singly, demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM after the exclusion of afatinib from the analysis (HR 0.56, 95% CI 0.35-0.90; P = 0.016). No statistically significant differences in OS were observed between the comparison groups. Conclusions: A trend in PFS favoring TKI-containing regimens was observed in patients with BM. Sensitivity analysis including only trials that evaluated regimens containing tucatinib, lapatinib, or pyrotinib demonstrated a significant PFS benefit favoring TK, SCOPUS: re.j, info:eu-repo/semantics/published