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Background: HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC. First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I-II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression., Methods: This phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+  locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes., Discussion: heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC., Trial Registration: ClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022)., Sponsor: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland., (© 2024. The Author(s).)

Purpose: To assess whether erythropoiesis-stimulating agents (ESA) administration impacts the outcomes of patients with HER2-positive early breast cancer (EBC)., Methods: ALTTO (NCT00490139) patients were categorized by ESA use during adjuvant anti-HER2 treatment. Disease-free-survival (DFS), overall survival (OS), and time-to-distant recurrence (TTDR) were analyzed by ESA administration, with subgroup analyses according to prognostic factors. Log-rank tests and Cox modeling were performed. Adverse events (AEs) of ESA-interest were compared., Results: Among 8381 patients recruited in ALTTO, 123 (1.5%) received ESA concomitantly with study treatment. The median age of patients receiving ESA was 54 years, 39.0% premenopausal, most had tumor size > 2 cm (56.9%), node-positive (58.5%), and positive estrogen receptor expression (61.8%). Median follow-up was shorter in the ESA group [6.1 years (IQR 5.3-7.0) vs. 6.9 years (6.0-7.1); p < 0.001]. There was no DFS difference by ESA administration (log-rank p = 0.70), with 3- and 7-year DFS of 89.2% (95% CI 81.8-93.8%) and 81.6% (71.4-88.5%) in ESA group vs. 88.3% (87.6-89.0%) and 80.0% (79.1-80.9%) in No-ESA group. In subgroup analyses, the interaction of ESA administration with menopausal status was statistically significant (unadjusted p = 0.024; stratified p = 0.033), favoring premenopausal women receiving ESA. We observed no significant association of ESA administration with OS (log-rank p = 0.57; 7-year OS in ESA 88.6% vs. 90.0% in non-ESA) or TTDR. ESA-interest AEs were experienced by eight (6.5%) patients receiving ESA and 417 (5.1%) in the No-ESA group (p = 0.41)., Conclusion: ESA administration to patients receiving adjuvant anti-HER2 treatment for HER2-positive EBC was safe and not associated with a negative impact on survival outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD73 antibody oleclumab in combination with the anti-PD-L1 durvalumab and 12 cycles of weekly carboplatin and paclitaxel. In the phase II part, 127 women were randomized 1:1 to receive chemo-immunotherapy, with (arm A) or without (arm B) oleclumab. The primary endpoint was the clinical benefit rate at week 24, defined as stable disease, partial or complete response per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, survival outcomes (progression-free survival and overall survival), and safety. The trial did not meet its primary endpoint, as the 24-week clinical benefit rate was not significantly improved by adding oleclumab (43% vs. 44%, p = 0.61). Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B (p = 0.90). The safety profile was manageable in both arms., (© 2023. The Author(s).)

Background: Patients with small node-negative HER2-positive breast cancer are commonly treated with paclitaxel and 1 year of adjuvant trastuzumab. We performed a sub-analysis of the ALTTO trial to explore the long-term outcomes of patients with small node-negative tumours., Methods: The ALTTO trial randomised 8381 patients with early HER2-positive BC treated with adjuvant chemotherapy (anthracycline/taxane- or taxane/carboplatin-based), to trastuzumab (T), lapatinib (L), their sequence (T → L) or their combination (L + T). Patients with tumours ≤3 cm and node-negative were included in this sub-analysis., Results: A total of 2821 patients were analysed (median follow-up of 7 years). The median age was 52 years, and most patients had tumours ≤2 cm (64.3%). The 7-year disease-free survival (DFS) was 88.1% (95% CI: 86.7-89.3%). DFS was similar for arms T, T + L and T⟶L and significantly lower for arm L (stratified log-rank P = 0.031). The 7-year overall survival rate was 95.9% (95% CI: [95.0-96.6%) and the 7-year time-to-distant recurrence was 93.4% (95% CI: 92.3-94.4%)., Conclusion: With most patients treated with anthracycline-based regimens, ALTTO shows that patients with small tumours treated with trastuzumab and concomitant chemotherapy have excellent long-term outcomes, similar to those of the APT trial., Trial Registration: Clinicaltrials.gov identifier NCT00490139., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients., Methods: Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)-positive populations., Results: At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference -0.33%; 95% CI, -9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1-positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference -8.26%; 95% CI, -20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies., Conclusion: Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide-paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1-positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

BERENICE (NCT02132949) assessed the cardiac safety of the neoadjuvant−adjuvant pertuzumab−trastuzumab-based therapy for high-risk, HER2-positive early breast cancer (EBC). We describe key secondary objectives at final analysis. Eligible patients received dose-dense doxorubicin and cyclophosphamide q2w × 4 ➝ paclitaxel qw × 12 (Cohort A) or 5-fluorouracil, epirubicin, cyclophosphamide q3w × 4 ➝ docetaxel q3w × 4 (B) as per physician’s choice. Pertuzumab−trastuzumab (q3w) was initiated from the taxane start and continued post-surgery to complete 1 year. Median follow-up: 64.5 months. There were no new cardiac issues and a low incidence of Class III/IV heart failure (Cohort B only: one patient (0.5%) in the adjuvant and treatment-free follow-up (TFFU) periods). Fourteen patients (7.7%) had LVEF declines of ≥10% points from baseline to <50% in Cohort A, as did 20 (10.5%) in B during the adjuvant period (12 (6.2%) in A and 7 (3.6%) in B during TFFU). The five-year event-free survival rates in Cohorts A and B were 90.8% (95% CI: 86.5, 95.2) and 89.2% (84.8, 93.6), respectively. The five-year overall survival rates were 96.1% (95% CI: 93.3, 98.9) and 93.8% (90.3, 97.2), respectively. The final analysis of BERENICE further supports pertuzumab−trastuzumab-based therapies as standard of care for high-risk, HER2-positive EBC.

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., Competing Interests: MAF, OE, DP, SG and LR: none. CT: Travel grant, Roche; advisory board: AstraZeneca, Eisai, Daiichi Sankyo, MSD. Speaker: Pfizer and Eisai. MP: MP’s institution received funding from Roche in respect of the APHINITY trial. NP: advisory board: Lilly; contracted research: Novartis, AstraZeneca, Daichii Sankyo, Roche and Pfizer; speaker: Novartis, Lilly, AstraZeneca and Roche. DE: funding for his research fellowship (2018–2019): Novartis; speaker fee: Janssen; salary paid by Roche. EA: honoraria and/or advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac and Libbs; travel grants from Roche/GNE and GSK/Novartis; research grant to my institution from Roche/GNE, Astra-Zeneca, GSK/Novartis and Servier. JB: travel expenses: AstraZeneca and Roche; consultant: AstraZeneca, Daiichi Sankyo, Genomic Health, Libbs, Lilly MSD, Novartis, Pfizer and Roche. EC: employee of Roche Products Ltd; issued patent: Uses for and article of manufacture including HER2 dimerisation inhibitor pertuzumab, 13/649591., (© the authors; licensee ecancermedicalscience.)

Background: Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC., Methods: The Neo-CheckRay trial is a randomized phase II trial investigating the impact of stereotactic body radiation therapy (SBRT) to the primary breast tumor in combination with an anti-CD73 (oleclumab) to increase response to anti PD-L1 (durvalumab) and NACT. The trial is designed as a three-arm study: NACT + SBRT +/- durvalumab +/- oleclumab. The result at surgery will be evaluated using the residual cancer burden (RCB) index as the primary endpoint. Six patients will be included in a safety run-in, followed by a randomized phase II trial that will include 136 evaluable patients in 3 arms. Inclusion is limited to luminal B breast cancers that are MammaPrint genomic high risk., Discussion: combination of ICB with chemotherapy in luminal B BC might benefit from immune priming agents to increase the response rate. As none have been identified so far, this phase II trial will evaluate SBRT and oleclumab as potential immune priming candidates., Trial Registration: trial registered on ClinicalTrials.gov ( NCT03875573 ) on March 14th, 2019., (© 2021. The Author(s).)

Background/methods: Although the prognosis of metastatic breast cancer (BC) has improved, some patients still develop high burden metastases or visceral crisis (VC) and polychemotherapy is commonly used in these cases. Data reporting the real effectiveness of this strategy are scanty. Therefore, the outcomes of patients with metastatic BC treated with platinum-based chemotherapy (P-ChT) at the Jules Bordet Institute during the period of January 2008 and December 2018 were retrospectively reviewed. The presence of VC was defined according to ABC 4 criteria., Results: 441 patients were identified: visceral metastases were observed in 430 (97.5%) while 261 (59.2%) presented VC. As for metastatic BC subtype, 255 (57.8%) had ER-positive/HER2-negative, 41 (9.3%) ER-positive/HER2-positive, 34 (7.7%) ER-negative/HER2-positive and 111 (25.1%) triple-negative BC. Median number of prior treatment lines was 3.8 (0-12). Median OS with P-ChT in the entire cohort was 6.13 months. Patients with VC had lower OS than patients without VC (8.6 vs 3.7 months; p < 0.001). On multivariate analysis, the variables correlated with worse OS were hyperbilirubinemia (HR 1.90; 95% CI 1.34-2.75), ECOG ≥2 (HR 1.77; 95% CI 1.13-2.78) and ECOG ≥3 (HR 2.52; 95% CI 1.48-4.28), and >3 previous treatment lines (HR 2.27; 95% CI 1.53-3.21). Of the 261 patients with VC, 106 (40.5%) presented a resolution of the VC which correlated with better OS (9.3 vs 2.0 months, HR 0.27; 95% CI 0.21-0.36)., Conclusion: Patients who overcome VC benefit from P-ChT with OS similar to patients without VC. In this analysis, hyperbilirubinemia, poor ECOG and >3 previous treatment lines were significant prognostic factors in the overall study population., Competing Interests: Declaration of competing interest MAF: none. RSC, SF: Travel grant from Pfizer for the ESMO conference 2019. DE: Funding for his fellowship (2018–2019: Novartis. Speaker fee: Janssen. AA: Advisory role, speaker fees and research funding for his institute from: Roche, Lilly, Amgen, EISAI, BMS, Pfizer, Novartis, MSD, Genomic Health, Ipsen, AstraZeneca, Bayer, Leo Pharma. EA: honoraria and advisory board: Roche/GNE, Novartis, Seattle Genetics and Zodiacs; travel grants: Roche/GNE, GSK/Novartis; co-principal investigator of the LORELEI trial (NCT02273973). Research grant for his institute: Roche/GNE, Astra-Zeneca, Novartis, and Servier., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) may cause potentially life-threatening adverse events (AEs), but the risk of cardiotoxicity has not been fully investigated. It is also unknown whether ICI combinations increase cardiotoxicity compared with single ICI. We aimed to assess the cardiotoxicity of ICI in a range of tumour types., Methods: This systematic review and meta-analysis was conducted according to PRISMA guidelines (PROSPERO registration number: CRD42020183524). A systematic search of PubMed, MEDLINE, Embase databases, and conference proceedings was performed up to 30 June 2020. All randomised clinical trials comparing ICI with other treatments (primary objective) or dual-agent ICI versus single-agent ICI (secondary objective) in any solid tumour were included. Pooled risk ratios (RRs) with 95% confidence intervals (95% CIs) for cardiotoxicity events were calculated using random effect models., Results: Eighty studies including 35,337 patients were included in the analysis (66 studies with 34,664 patients for the primary endpoint and 14 studies with 673 patients for the secondary endpoint). No significant differences in terms of cardiac AEs were observed between ICI and non-ICI groups (RR 1.14, 95% CI 0.88-1.48, p = 0.326) nor between dual ICI and single ICI groups (RR 1.91, 95% CI 0.52-7.01, p = 0.329). Myocarditis incidence did not significantly differ between ICI and non-ICI groups (RR 1.11, 95% CI 0.64-1.92, p = 0.701) nor between dual ICI and single ICI groups (RR 1.10, 95% CI 0.31-3.87, p = 0.881). No differences were observed in subgroup analyses according to tumour type, setting of disease, treatment line, and type of treatment., Conclusion: The use of ICI as single or combination regimens is not associated with increased risk of cardiotoxicity., Competing Interests: Conflict of interest statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. EA, MC, and MB have no conflicts of interest to declare. DEF funding for his ESMO fellowship (2018–2019) from Novartis and received honoraria from Janssen for speaking (outside the submitted work). ML acted as a consultant for Roche and Novartis and received honoraria from Theramex, Takeda, Roche, Lilly, Pfizer, and Novartis (outside the submitted work). NP acted as a consultant for Lilly and has received honoraria from Roche, Lilly, Novartis, and AstraZeneca (outside the submitted work). CP has received honoraria for speaking at educational meetings from Amgen, Ferring, Incyte, Ipsen, Novartis, Pfizer, and Roche (outside the submitted work). AHA received advisory role, speaker fees, and research funding for his institute from Roche, Lilly, Amgen, EISAI, BMS, Pfizer, Novartis, MSD, Genomic Health, Ipsen, AstraZeneca, Bayer, and Leo Pharma (outside the submitted work). AS is a member of the advisory boards at BMS, Servier, Gilead, Pfizer, Eisai, Bayer, and MSD; participated in conference at Takeda, Roche, AbbVie and Amgen, Celgene, AstraZeneca, Lilly, Sandoz, Novartis, BMS, Servier, Gilead, Pfizer, ArQule, and Eisai; and was a consultant at ArQule (outside the submitted work). MP was a board member (Scientific Board) at Oncolytics, Radius; was a consultant (honoraria) at AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche, and Seattle Genetics; and received grants to her institute from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, and Synthon (outside the submitted work). EdA received honoraria from and was a member of advisory board at Roche/GNE, Novartis, Seattle Genetics, Zodiacs, Libbs, and Pierre Fabre; received travel grants from Roche/GNE and GSK/Novartis; received grant for his institute from Roche/GNE, Astra-Zeneca, Novartis, and Servier (outside the submitted work)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: There are limited data regarding the impact of body mass index (BMI) on outcomes in advanced breast cancer, especially in patients treated with endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitors., Methods: A pooled analysis of individual patient-level data from MONARCH 2 and 3 trials was performed. Patients were classified according to baseline BMI into underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2) and divided into 2 treatment groups: abemaciclib + ET vs placebo + ET. The primary endpoint was progression-free survival (PFS) according to BMI in each treatment group. Secondary endpoints were response rate, adverse events according to BMI, and loss of weight (≥5% from baseline) during treatment., Results: This analysis included 1138 patients (757 received abemaciclib + ET and 381 placebo + ET). There was no difference in PFS between BMI categories in either group, although normal-weight patients presented a numerically higher benefit with abemaciclib + ET (Pinteraction = .07). Normal and/or underweight patients presented higher overall response rate in the abemaciclib + ET group compared with overweight and/or obese patients (49.4% vs 41.6%, odds ratio = 0.73, 95% confidence interval = 0.54 to 0.99) as well as higher neutropenia frequency (51.0% vs 40.4%, P = .004). Weight loss was more frequent in the abemaciclib + ET group (odds ratio = 3.23, 95% confidence interval = 2.09 to 5.01)., Conclusions: Adding abemaciclib to ET prolongs PFS regardless of BMI, showing that overweight or obese patients also benefit from this regimen. Our results elicit the possibility of a better effect of abemaciclib in normal and/or underweight patients compared with overweight and/or obese patients. More studies analyzing body composition parameters in patients under treatment with cyclin-dependent kinase 4/6 inhibitors may further clarify this hypothesis., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of Review: Triple negative breast cancer (TNBC) accounts for approximately 10-15% of all breast cancers and it is associated with a poor prognosis. However, recent new effective treatment strategies have improved its outcomes. The aim of this review is to provide an overview on the emerging therapeutics for TNBC, describing both previously approved therapies that are currently being repurposed, as well as new target therapies that may improve patient outcomes., Recent Findings: Emerging therapies are forthcoming in TNBC's treatment landscape, including new post-neoadjuvant chemotherapy strategies, PARP inhibitors, immune checkpoint inhibitors, and antibody-drug conjugates. Combination of different therapies such as AKT/PI3K/mTOR-inhibitors, other immunotherapeutic agents, CDK-inhibitors, antiandrogens, antiangiogenics, and histone deacetylase inhibitors is under clinical investigation. The treatment landscape for TNBC is gradually evolving towards a more personalized approach with promising expectations.

Background: As women living with HIV (WLWH) become older, their risk of developing breast cancer increases. Nonetheless, literature is conflicting regarding tumor stage, distribution of subtypes and overall survival among WLWH vs. HIV-negative women with breast cancer. We assessed differences in clinicopathological characteristics and overall survival between these two groups., Methods: Systematic review and meta-analysis using MEDLINE, Scopus, ISI Web of Knowledge, LILACS, SciELO and conference abstracts up to 1 January 2020. Cross-sectional/cohort studies comparing baseline characteristics (stage and/or subtypes) and/or overall survival of WLWH vs. HIV-negative women with breast cancer were included. We performed random-effects meta-analyses to estimate summary statistics and subgroup analyses according to region of the world., Results: Eighteen studies [4 from North America, 14 from sub-Saharan Africa (SSA)] were included, with 3174 WLWH and 2 394 598 HIV-negative women. WLWH from North America and SSA were more likely to present with stage III/IV disease compared with HIV-negative women - pooled odds ratio (pOR) 1.76 [95% confidence interval (CI):1.58-1.95] and pOR 1.23 (95% CI: 1.06-1.42), respectively. WLWH from SSA were also less likely to have estrogen receptor-positive/HER2-negative tumors (pOR 0.81; 95% CI: 0.66-0.99). After adjustment, WLWH had worse overall survival compared with HIV-negative women, both in North America [pooled adjusted hazard ratio (aHR) 2.45; 95% CI: 1.11-5.41] and SSA (aHR 1.43; 95% CI: 1.06-1.92)., Conclusion: Compared with HIV-negative women, WLWH are diagnosed with breast cancer at a more advanced stage and have a worse overall survival. These results should raise awareness regarding the detection and survival gap among WLWH with breast cancer and further studies are needed to decipher the reasons behind these disparities., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Since human epidermal growth factor receptor-2 (HER2) characterization, going through clinical research and regulatory approval of HER2-targeted therapies, much has elapsed and is still unfolding. Hitherto, only breast cancer (BC) patients with HER2 immunohistochemistry 3+ or with HER2 gene fluorescence in-situ hybridization (FISH) amplification (a.k.a., HER2-positive BC) have benefited from anti-HER2 agents. In recent years, however, much of the research effort has been expanded, with positive outcomes being reached for formerly known HER2-negative BC that yet express HER2 to some degree (HER2 immunohistochemistry 1+ or 2+, but FISH negative) and are currently being classified as HER2-low BC for the purpose of trial enrollment. In this sense, our aim is to review the body of evidence of HER2-low BC that led to the study of first-generation anti-HER2 agents, like trastuzumab, and how they have failed to achieve any clinical applicability in this setting. In addition, we review new data that is leading to the growing success of the new generation of drugs, especially the promising HER2-directed antibody-drug conjugates. A narrative review is also performed regarding the rationale behind the consolidated and ongoing clinical trials studying anti-HER2 agents in combination with unrelated agents, such as immunotherapy, endocrine therapy, and CDK4/6 inhibitors. Hopefully, all this ongoing research effort will be able to extend the survival benefits seen with anti-HER2 agents in HER2-positive disease, at least to some degree, to the greater proportion of patients with HER2-low BC.

Purpose: Body composition parameters including muscle and adipose tissue measurements have emerged as prognostic factors in cancer patients. Besides cell cycle regulation, CDK 4 and 6 also control metabolic processes (lipid synthesis, glycolysis, and mitochondrial function). We studied the impact of baseline body composition parameters on response to CDK 4/6 inhibition and changes on body composition during treatment., Methods: Retrospective study of 50 patients treated at Institut Jules Bordet between December 2016 and August 2019 with endocrine therapy and CDK 4/6 inhibitor as first or second-line treatment for metastatic breast cancer (BC). CT-based body composition analysis was performed at 3 time points. Cox regression and Kaplan-Meier method were used for the association with Progression-free survival (PFS). Changes in body composition parameters were described in means and compared using paired sampled T test., Results: Baseline sarcopenia was present in 40% of patients and associated with a significantly worse PFS compared to patients without sarcopenia (20.8 vs 9.6 months, HR 2.52; 95% CI 1.02-6.19, p = 0.037). Patients with higher visceral fat index and higher visceral fat density had better PFS (20.8 vs 10.4 months, HR 0.40; 95% CI 0.16-0.99 p = 0.041-stratified for treatment line). No significant alterations in body composition parameters during treatment were observed., Conclusion: Sarcopenia is a potential early marker of poor prognosis among patients with metastatic BC treated with CDK 4/6 inhibitors. CT scan evaluation of sarcopenia and adiposity revealed significant prognostic information. Visceral fat could also play an important role in response to CDK 4/6 inhibitors, deserving further investigation.

Background: Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting., Methods: This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm., Results: With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m 2 (vs < 25 mg/kg 2 , OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m 2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m 2 (OR 2.33 [95% CI 1.55-3.51])., Conclusions: Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial., Trial Registration Number: ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

Purpose: In early-stage breast cancer, steatotic liver disease (SLD) is associated with increased recurrence, cardiovascular events, and non-cancer death. Endocrine therapy (ET) increases the risk of SLD. The impact of cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) on SLD and prognostic association in metastatic breast cancer is unknown. We characterized the presence of SLD, risk factors, and treatment outcomes of SLD in metastatic HR+/HER2- breast cancer receiving CDK4/6i., Methods: This single institution, retrospective, cohort study included patients with metastatic HR+/HER2- breast cancer receiving first-line ET and CDK4/6i from January 2018 to June 2022. SLD was defined as a Liver Attenuation Index (LAI) > 25 HU on contrast-enhanced CT scans and/or > 10 HU on plain CT scans. Univariable binary-logistic regression was used to assess associations with SLD. Time to treatment failure (TTF) and overall survival (OS) were analyzed using Cox proportional hazards modeling., Results: Among 87 patients with a median age of 58 years and 65.5% postmenopausal, 50 (57.5%) had SLD at anytime (24 at baseline, 26 acquired). SLD at baseline was statistically associated with post-menopausal status. It was quantitatively but not statistically associated with age > 65, diabetes, smoking, and HER2-low. SLD at anytime was statistically significantly associated with longer TTF (median 470 vs 830.5 days, HR = 0.38, p < 0.001). No significant differences in OS or grade 3/4 adverse events were observed between groups., Conclusion: This study demonstrated a high prevalence of SLD in this population, with SLD presence correlated with longer TTF. SLD may be an indicator of better outcomes in metastatic HR+/HER2- breast cancer patients treated with CDK4/6i., Competing Interests: Declarations. Conflict of interest: Dr. Diego Malon reports honoraria/speaking fee from Bristol Meyers Squibb. Dr. Consolacion Molto reports honoraria/speaking fees from AstraZeneca and Merck. Dr. Eitan Amir reports honoraria/consulting or Advisory role fees from Seagen, Gilead, AstraZeneca and Novartis. Dr. Nadler reports speaker honorarium and consulting fees from Novartis and Exact Sciences. All of them outside of the scope of this submitted work. No Conflict of Interest for Shopnil Prasla, Danielle Cuthbert, Neha Pathak, Yael Berner-Wygoda, Massimo Di lorio, Meredith Li, Jacqueline Savill, Abhenil Mittal and Kartik Jhaveri. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki and The University Health Network Research Ethics Board approval was obtained (Approval Number 22-5856). Consent to participate: Due to the characteristics of the study written informed consent of the participants is not required. A waiver of consent will not adversely affect the rights and welfare of the subjects. This research will not affect clinical care of the individuals., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Treatment de-escalation in early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been attempted in order to decrease costs and toxicities. One of the strategies pursued is decreasing trastuzumab treatment duration, with mixed results thus far. Trastuzumab-associated cardiotoxicity, however, may be more frequent with 12 months of trastuzumab compared with shorter treatment lengths. Therefore, we have conducted a meta-analysis to address this question., Materials and Methods: A meta-analysis of trials testing 12 months of adjuvant trastuzumab versus shorter regimens, reporting cardiac outcomes in patients with HER2-positive BC was performed with the random effects model with inverse variance weighting., Results: Clinical cardiac dysfunction associated with 12 months of trastuzumab versus shorter trastuzumab regimens, including 11 250 patients, showed a pooled OR (pOR) of 1.90 (95% CI 1.37 to 2.64; p value <0.001; I 2 =65.7%); in the subgroup comparison of 12 versus 6 months, the pOR was 1.57 (95% CI 1.30 to 1.90; p<0.001; I 2 =5.7%). pOR for low left ventricular ejection fraction was 1.45 (95% CI 1.19 to 1.75; p<0.001; I 2 =11.9%), 1.55 (95% CI 1.00 to 2.42; p=0.052; I 2 =0.0%) for congestive heart failure and 3.70 (95% CI 0.27 to 51.60; p=0.33; I 2 =78.8%) for premature trastuzumab discontinuation due to cardiotoxicity for 12 months versus shorter trastuzumab regimens. Funnel plot analyses indicated a low risk of publication bias., Conclusions: Compared to shorter treatment durations, there is sufficient evidence that 12 months of trastuzumab yields higher odds for the occurrence of relevant cardiac events. An individual patient-level data meta-analysis is needed in order to provide adequate data on risk factors for cardiotoxicity., Competing Interests: Competing interests: DE: funding for his fellowship: Novartis. Research grant for his institute: Roche/GNE, Radius, AstraZeneca, Lilly, MSD, Novartis, Synthon, Servier and Pfizer. MAF: research grant for her institute: Roche/GNE, Radius, AstraZeneca, Lilly, MSD, Novartis, Synthon, Servier and Pfizer. NFP: honoraria: MundiPharma, AstraZeneca; travel grants: Novartis, Astrazeneca, MundiPharma, Roche. MB: research grant for her institute: Roche/GNE, Radius, AstraZeneca, Lilly, MSD, Novartis, Synthon, Servier and Pfizer. EdA: honoraria and advisory board: Roche/GNE, Novartis, Seatle Genetics; travel grants: Roche/GNE, GSK/Novartis; co-principal investigator of the LORELEI trial (NCT02273973). Research grant for his institute: Roche/GNE, AstraZeneca, Novartis and Servier., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Although the prognosis of HER2-positive breast cancer patients has dramatically improved with modern chemotherapy and the monoclonal antibody trastuzumab, up to 31% of them will experience a recurrence in the long term. After the unprecedented benefit in overall survival with the addition of the second monoclonal antibody pertuzumab for patients with metastatic disease, the drug was tested with various degrees of success in the preoperative and postoperative settings. In this review, we will focus on the pharmacologic aspects of the drug, including mechanism of action and toxicities, and discuss clinical data regarding its use in advanced and early stage HER2-positive breast cancer, placing in perspective the pros and cons regarding other available drugs and biomarkers.

Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR-biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

In this Letter to the Editor, Agrawal et al . debate the conflicts that can arise regarding the authorship of case reports. Like all other medical journals, EJCRIM has zero tolerance for the willful undisclosed re-submission of papers that have already been published elsewhere. However, this may occasionally happen by accident, especially in large healthcare institutions in which multiple teams of physicians may care for a patient throughout their illness. EJCRIM endorses and recommends to all potential authors the very sensible suggestions made by Agrawal et al . to avoid such an error occurring. EJCRIM would also encourage authors to consider the following: The first author should ensure that no one else involved in the case has reported it or plans to report it. This is especially important for physicians working in large healthcare centres, and/or for case reports of patients who have been under investigation or treatment for prolonged periods.On rare occasions EJCRIM will consider a case that has already been published, provided that this is fully and explicitly disclosed, and there is a clear reason why re-publication is justified. An example might be where new information has come to light that significantly changes the conclusions of the original report. As in all reports published by EJCRIM the decision to publish will depend on the educational value, or learning points, of the case., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests.