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The primary objective of this study was to identify intravenous regimens of tipifarnib that would mimic the systemic exposure obtained after the current twice-daily oral administration of tipifarnib. After determination of an intravenous dose that 6 subjects with advanced cancer could tolerate, another 26 subjects were randomly assigned to receive 3 consecutive 4-day regimens of tipifarnib with different treatment sequences: a 100-mg 2-hour intravenous infusion, 200-mg oral administration twice daily, and a 200-mg/d continuous intravenous infusion. The systemic exposure to tipifarnib was comparable among these 3 regimens. The plasma concentration-time profile of 2-hour intravenous infusion more closely resembled the oral administration than did the continuous infusion. Glu-curonidation is a metabolic pathway for tipifarnib with concentrations of the glucuronide conjugate greatly exceeding the parent compound after oral and intravenous administration. Analysis of plasma metabolites indicated that tipifarnib also undergoes dealkylation and loss of the imidazole group. [ABSTRACT FROM AUTHOR]

Background: One year (yr) of trastuzumab (T) significantly improves disease-free (DFS) and overall survival (OS) in patients with HER2-positive early breast cancer (EBC) and is considered the standard of care. HERA is the only randomized trial investigating whether longer duration of T can further improve efficacy outcome. Materials and Methods: HERA (BIG 01-01) is an international, multicenter, phase III randomized trial involving 5102 women with HER2-positive EBC. Pts were randomized, after completion of primary therapy [surgery, chemotherapy and radiotherapy as indicated], to T every 3 weeks for 1 yr , 2 years (yrs), or observation. This landmark efficacy analysis compares the outcome of pts randomized to either 2 yrs or 1 yr of T who were disease-free at 1 yr after randomization (N = 1553 for 2 yrs, and N=1552 for 1 yr). The primary endpoint is DFS and secondary endpoints are OS and time to distant recurrence (TTDR). Updated efficacy analyses of the T arms vs. observation at 8-yrs of median follow-up (FU) are also presented. Results: On 12 April 2012 HERA reached the target number of 725 DFS events needed for 80% power to detect a true hazard ratio (HR) of 0.80 for the comparison of 2 yrs vs. 1 yr of T. The unadjusted HR for an event in the 2-yr vs. 1-yr T arms was 0.99 (95% CI 0.85-1.14; p = 0.86). OS in the two arms was comparable [HR=1.05 (95% CI 0.86-1.28; p = 0.63)]. TTDR results were similar . The primary cardiac endpoint* was comparable (1.0% vs. 0.8% for 2-yr and 1-yr arms, respectively), but the secondary cardiac endpoint** was higher in the 2-yr arm (7.2% vs. 4.1%). Importantly , the durable benefit in DFS and OS for both 1 yr and 2 yrs of T compared with observation remains stable at 8 yrs of median FU. Subgroup analyses including by hormone receptor status will be available for the meeting. Conclusions: These results confirm that 1 yr of adjuvant T remains the standard of care for HER2-positive EBC pts. It is also reassuring that the significant improvement in DFS and OS persists over time and that the incidence of cardiac endpoints remains low at a median FU of 8 yrs. * NYHA class III or IV, confirmed by a cardiologist, and LVEF < 50% and 10% below baseline, OR cardiac death. ** LVEF < 50% and ≥10% below baseline confirmed by repeat assessment, excluding patients with a primary cardiac endpoint. [ABSTRACT FROM AUTHOR]

Background: Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy. Materials and methods: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material. According to the availability of tumor material, samples were characterized using a 120 mutational hotspot qPCR, a 29 gene copy number aberrations (CNA) and a 400 gene expression panels. ESR1 mutations were assayed by droplet digital PCR. Molecular alterations were correlated with overall survival (OS) using the Cox proportional hazards regression models. Results: The median follow-up was 6.4 years (range 0.5-26.6 years). Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. Mutations and CN amplifications were largely concordant between P and matched M (>84%). ESR1 mutations were found in 10.8% of the M but none of the P. Thirteen genes, among which ESR1, FOXA1, and HIF1A, showed significant differential expression between P and M. In P, the differential expression of 18 genes, among which IDO1, was significantly associated with OS (FDR < 0.1). Conclusions: Despite the large concordance between P and matched M for the evaluated molecular alterations, potential actionable targets such as ESR1 mutations were found only in M. This supports the importance of characterizing the M disease. Other targets we identified, such as HIF1A and IDO1, warrant further investigation in this patient population. [ABSTRACT FROM AUTHOR]

Background: Afatinib is a ErbB Family Blocker that irreversibly blocks signaling from all relevant ErbB Family dimers. Afatinib is being developed in EGFR (ErbB1)-driven (non-small cell lung cancer [NSCLC]/head and neck squamous cell carcinoma) and HER2 (ErbB2)-driven (breast) malignancies, and has shown clinical efficacy in NSCLC patients with EGFR activating mutations.1,2 In trastuzumab-resistant, HER2-positive (SUM190) xenografts, afatinib showed antitumor activity which was superior to lapatinib. Afatinib monotherapy activity in this SUM190 model was increased by the addition of intravenous (i.v.) vinorelbine. Clinically, afatinib monotherapy demonstrated activity in an open-label, single-arm, Phase II trial in patients with HER2-positive MBC after progression on trastuzumab, with a progression-free survival (PFS) of 15.1 weeks, an overall survival (OS) of 61.0 weeks and 10% objective response (OR).3 HER -reprogramming appears to play an important role in resistance4 and recent clinical trial results have indicated that targeting more than one ErbB Family member increases efficacy.5 Thus afatinib, as an ErbB Family Blocker, should add to the portfolio of drugs available to treat trastuzumab resistance in HER2-positive BC patients. This is currently being tested in the LUX -Breast 1 trial. Methods: LUX-Breast 1 (NCT01125566 ) is a Phase III, open-label, multicenter trial evaluating the efficacy and safety of afatinib + vinorelbine vs. trastuzumab + vinorelbine in patients with HER2-overexpressing MBC who progressed on, or after one prior trastuzumab-based treatment regimen. Patients are randomized 2:1 to afatinib (40 mg/day oral) + vinorelbine (i.v. 25 mg/m²/week) or trastuzumab (i.v. 2 mg/kg/week after 4 mg/kg loading dose) + vinorelbine (i.v. 25 mg/m²/week). Patients receive continuous treatment in the absence of disease progression or unacceptable toxicity. Key eligibility criteria include histologically-confirmed HER2-positive MBC; no prior treatment with vinorelbine or HER2-targeted treatment other than trastuzumab; progression on one prior trastuzumab based regimen in either the adjuvant (or <12 months after trastuzumab completion) or first-line (or <6 months after trastuzumab completion) setting; prior anthracycline and/or taxane chemotherapy and an ECOG score of 0 or 1. The primary endpoint is PFS and secondary endpoints include OR, OS and safety. Patients' quality of life will be evaluated alongside other endpoints. Biomarkers will be assessed on archival tissue, in serum and in voluntary fresh tissue biopsies. Analyses on fresh tissue biopsies include ErbB-receptor and ErbB-ligand reprogramming, putative resistance markers, and EGF response signature. Enrollment began in June 2010 and is ongoing, targeting >240 sites with a recruitment target of 780 patients. 1. Yang JCH. Lancet Oncol 2012;13:539-48. 2. Yang JCH. J Clin Oncol 2012;30(suppl; abstr LBA7500). 3. Lin NU, et al. Breast Cancer Res Treat 2012. DOI: 10.1007/s10549-012- 2003-y. 4. Metro G, et al. Expert Opin Pharmacother 2008;9:2583-601. 5. Bischoff J and Ignatov A. Breast Care 2010;5:134-41. [ABSTRACT FROM AUTHOR]

Background: Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial., Patients and Methods: The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), time to distant recurrence and safety., Results: Overall, 6281 patients with HER2-positive early breast cancer were included in the final efficacy analysis in three treatment groups: trastuzumab (T), lapatinib + trastuzumab (L + T) and trastuzumab followed by lapatinib (T→L). Baseline characteristics were well balanced between groups. At a median follow-up of 9.8 years, the addition of lapatinib to trastuzumab and chemotherapy did not significantly improve DFS nor OS. The 10-year DFS was 77% in T, 79% in L + T and 79% in T→L, and the 10-year OS was 87%, 89% and 89%, respectively. The incidence of any cardiac event was low and similar in the three treatment groups., Conclusions: With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physician's choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

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.)

Efficacy of the human epidermal growth factor receptor (HER)2-targeting trastuzumab emtansine (T-DM1) in breast cancer (BC) relies on HER2 status determined by immunohistochemistry or fluorescence in-situ hybridization. Heterogeneity in HER2 expression, however, generates interest in "whole-body" assessment of HER2 status using molecular imaging. We evaluated the role of HER2-targeted molecular imaging in detecting HER2-positive BC lesions and patients unlikely to respond to T-DM1. Patients underwent zirconium-89 ( 89 Zr) trastuzumab (HER2) PET/CT and [ 18 F]-2-fluoro-2-deoxy-D-glucose (FDG) PET/CT before T-DM1 initiation. Based on 89 Zr-trastuzumab uptake, lesions were visually classified as HER2-positive (visible/high uptake) or HER2-negative (background/close to background activity). According to proportion of FDG-avid tumor load showing 89 Zr-trastuzumab uptake (entire/dominant part or minor/no part), patients were classified as HER2-positive and HER2-negative, respectively. Out of 265 measurable lesions, 93 (35%) were HER2-negative, distributed among 42 of the 90 included patients. Of these, 18 (19%) lesions belonging to 11 patients responded anatomically (>30% decrease in axial diameter from baseline) after three T-DM1 cycles, resulting in an 81% negative predictive value (NPV) of the HER2 PET/CT. In combination with early metabolic response assessment on FDG PET/CT performed before the second T-DM1 cycle, NPVs of 91% and 100% were reached in predicting lesion-based and patient-based (RECIST1.1) response, respectively. Therefore, HER2 PET/CT, alone or in combination with early FDG PET/CT, can successfully identify BC lesions and patients with a low probability of clinical benefit from T-DM1., (© 2024. The Author(s).)

Purpose: We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer., Methods: Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. "Surgery" group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis., Results: 1985 patients, 534 (26.9%) in the "Surgery" and 1451 (73.1%) in the "No Surgery" group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6-88.5). Median OS was 60.1 months (57.1-68.2) in the "Surgery" vs. 41.9 months (39.8-44.2) in the "No Surgery" group (adjusted HR 0.56; 0.49-0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings., Conclusion: Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Luminal B breast cancer (BC) presents a worse prognosis when compared with luminal A BC and exhibits a lower sensitivity to chemotherapy and a lower immunogenicity in contrast to non-luminal BC subtypes. The Neo-CheckRay clinical trial investigates the use of stereotactic body radiation therapy (SBRT) directed to the primary tumor in combination with the adenosine pathway inhibitor oleclumab to improve the response to neo-adjuvant immuno-chemotherapy in luminal B BC. The trial consists of a safety run-in followed by a randomized phase II trial. Here, we present the results of the first-in-human safety run-in., Methods: The safety run-in was an open-label, single-arm trial in which six patients with early-stage luminal B BC received the following neo-adjuvant regimen: paclitaxel q1w×12 → doxorubicin/cyclophosphamide q2w×4; durvalumab (anti-programmed cell death receptor ligand 1 (PD-L1)) q4w×5; oleclumab (anti-CD73) q2w×4 → q4w×3 and 3×8 Gy SBRT to the primary tumor at week 5. Surgery must be performed 2-6 weeks after primary systemic treatment and adjuvant therapy was given per local guidelines, RT boost to the tumor bed was not allowed. Key inclusion criteria were: luminal BC, Ki67≥15% or histological grade 3, MammaPrint high risk, tumor size≥1.5 cm. Primary tumor tissue samples were collected at three timepoints: baseline, 1 week after SBRT and at surgery. Tumor-infiltrating lymphocytes, PD-L1 and CD73 were evaluated at each timepoint, and residual cancer burden (RCB) was calculated at surgery., Results: Six patients were included between November 2019 and March 2020. Median age was 53 years, range 37-69. All patients received SBRT and underwent surgery 2-4 weeks after the last treatment. After a median follow-up time of 2 years after surgery, one grade 3 adverse event (AE) was reported: pericarditis with rapid resolution under corticosteroids. No grade 4-5 AE were documented. Overall cosmetical breast evaluation after surgery was 'excellent' in four patients and 'good' in two patients. RCB results were 2/6 RCB 0; 2/6 RCB 1; 1/6 RCB 2 and 1/6 RCB 3., Conclusions: This novel treatment combination was considered safe and is worth further investigation in a randomized phase II trial., Trial Registration Number: NCT03875573., Competing Interests: Competing interests: ADC: institutional, AstraZeneca. ER: institutional, BMS; institutional: AstraZeneca; institutional: Replimune. Research fundings: Fondation Amgen, Fondation BMS; travel grant from Roche, BMS, Merck. Research fundings: Amgen. AG: Financial Interests, Institutional, AstraZeneca; Financial Interests, Institutional: Daiichi. EA: Consultancy fees/honoraria: Eli Lilly, Sandoz, AstraZeneca. Institutional: Gilead. Support for attending medical conferences from: Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili, Daiichi Sankyo, AstraZeneca. DVG: Advisory board/Honoraria received: Sanofi, Accuray, Merck-Pfizer, Takeda and Novartis. MP: Board Member (Scientific Board): Oncolytics; Consultant (honoraria): AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Periphagen, Pfizer, Roche, Seattle Genetics. Research grants to my Institute: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genetech, Servier, Synthon. No stock ownership. DVG: Advisory board/Honoraria received: Sanofi, Accuray, Merck-Pfizer, Takeda and Novartis. RS: non-financial support from Merck, non-financial support from BMS, other from Puma Biotechnology, other from Roche, other from Roche, other from Merck. CS: Institutional: Astellas; Personal: Cepheid; Institutional: Vertex; Institutional: Seattle Genetics; Personal: Puma; Institutional: AMGEN; Personal: Eisai; Institutional, Other, Travel: Roche; Institutional, Other, Internal speaker: Genentech; Personal, Other, Regional speaker: Pfizer; Institutional: Inc.; Institutional: Exact Sciences; Institutional: Merck & Co; Personal: prIME Oncology, Personal: Teva. MP: Board Member (Scientific Board): Oncolytics; Consultant (honoraria): AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Periphagen, Pfizer, Roche, Seattle Genetics. Research grants to my Institute: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genetech, Servier, Synthon. No stock ownership. MI: Consultant or advisory role (honoraria): Celgene, Novartis, Pfizer, Seattle Genetics, Tesaro. Research grants to my Institute: Roche, Menarini Silicon Biosystems, Janssen Diagnostics, Pfizer. No stock ownership. Travel grants: Pfizer, Amgen. LB: institutional research grant from AstraZeneca; speaker honoraria from BMS, Novartis; travel grant from Roche, GILEAD. Advisory Board: Iteos, Domain Therapeutics. All other authors: no disclosures., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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).)

Triple-positive breast tumors overexpress human epidermal growth factor receptor 2 (HER2) and are positive for hormone receptor (HR) expression. Data from real-life and clinical trials show that estrogen receptor (ER) expression affects the response to combinations of anti-HER2 and associated systemic therapies. Despite triple-positive tumors having decreased response rates compared to HR-negative/HER2-positive breast cancers, optimizing anti-HER2 treatment with dual anti-HER2 blockade remains important for optimal disease control. Preclinical data on the cross-talk between ER and growth factor receptor pathways show the efficacy of combinations of endocrine therapy and anti-HER2 drugs, which is confirmed in the clinic. Molecular dissection of triple-positive breast cancer might provide the rational for additional therapeutic strategies and the identification of promising biomarkers. This review summarizes data on systemic treatment efficacy from major clinical trials and perspectives for future clinical research in triple-positive breast cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Recent progress in immunobiology has led the way to successful host immunity enhancement against breast cancer. In triple-negative breast cancer, the combination of cancer immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors with chemotherapy was effective both in advanced and early setting phase 3 clinical trials. These encouraging results lead to the first approvals of immune checkpoint inhibitors in triple-negative breast cancer and thus offer new therapeutic possibilities in aggressive tumors and hard-to-treat populations. Furthermore, several ongoing trials are investigating combining immunotherapies involving immune checkpoint inhibitors with conventional therapies and as well as with other immunotherapeutic strategies such as cancer vaccines, CAR-T cells, bispecific antibodies, and oncolytic viruses in all breast cancer subtypes. This review provides an overview of immunotherapies currently under clinical development and updated key results from clinical trials. Finally, we discuss the challenges to the successful implementation of immune treatment in managing breast cancer and their implications for the design of future clinical trials., (© 2023. The Author(s).)

Aim: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations., Methods: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention., Results: The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking., Conclusions: STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score., Trial Registration: clinicaltrials.gov Identifier NCT01358877., Competing Interests: Conflict of interest statement Richard D. Gelber: Research grants to institutions from Roche, Novartis, Pfizer, AstraZeneca, Merck. Xin Victoria Wang: None for this work. Bernard F. Cole: None for this work. David Cameron: Non-personal (all income to institution). Advisory/consultancy work with Roche, Novartis, Synthon, Seattle Genetics, Daiichi-Sankyo. Research funding during the life of APHINITY trial – Novartis and Roche. Stock ownership, expert testimony, directorships – NONE. Fatima Cardoso: Consultancy role for Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Debiopharm, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, IQVIA, MacroGenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, touchIME. Vivianne Tjan-Heijnen: Grants and personal fees from Pfizer, grants and personal fees from Roche, grants and personal fees from Novartis, grants and personal fees from E Lilly, grants from Eisai, grants and personal fees from Daiichi Sankyo, personal fees from Accord. Ian Krop: Research support (paid to his institution) from Genentech/Roche and Pfizer, has received fees from Novartis and Merck for Data Monitoring Board participation and has received consulting fees from Bristol Meyers Squibb, Daiichi/Sankyo, Macro-Genics, Context Therapeutics, Taiho Oncology, Genentech/Roche, Seattle Genetics, Celltrion and AstraZeneca. Sherene Loi: Research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech and Seattle Genetics. She has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics and Bristol Meyers Squibb. She has been a Scientific Advisory Board Member of Akamara Therapeutics. She is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. Roberto Salgado: Non-financial support from Merck and Bristol Myers Squibb; research support from Merck, Puma Biotechnology and Roche; advisory board fees for Bristol Myers Squibb; no COI related to this project. He is supported by a grant from the Breast Cancer Research Foundation (grant No. 17-194). Astrid Kiermaier: Employee and stockowner at F. Hoffmann-La Roche. Elizabeth Frank: None for this work. Debora Fumagalli: My institution received support from F. Hoffmann-La Roche Ltd/Genentech, Inc. for the conduct of APHINITY. My institution also receives support from F. Hoffmann-La Roche Ltd/Genentech, AstraZeneca, Novartis, Servier, Tesaro, Sanofi and Pfizer for the conduct of clinical trials. Carmela Caballero: My institution received support from F. Hoffmann-La Roche Ltd/Genentech, Inc. for the conduct of APHINITY. My institution also receives support from F. Hoffmann-La Roche Ltd/Genentech, AstraZeneca, Novartis, Servier, Tesaro, Sanofi and Pfizer for the conduct of clinical trials. Evandro Azambuja: Honoraria and/or advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac, Libbs, Lilly and Pierre Fabre; travel grants from Roche/GNE and GSK/Novartis; research grants to my institution from Roche/GNE, AstraZeneca, GSK/Novartis and Servier. Marion Procter: M.P.'s institution received funding from Roche in respect to the APHINITY trial. Emma Clark: Employee of Roche Products Ltd. Shares in F. Hoffmann-La Roche. Issued patent: uses for and article of manufacture including HER2 dimerisation inhibitor pertuzumab, 13/649591. Eleonora Restuccia: Employment by F. Hoffmann-La Roche and stocks in F. Hoffmann-La Roche/Genentech. Sarah Heeson: Employment by Roche Products Ltd and shares in F. Hoffmann-La Roche. Jose Bines: Dr. Bines reports personal fees from Roche during the conduct of the study. Sibylle Loibl: Dr. Loibl reports grants, non-financial support and other from Roche during the conduct of the study; grants and other from AbbVie, non-financial support and other from Amgen, grants and other from AstraZeneca, other from Bayer, other from BMS, grants and other from Celgene, grants, non-financial support and other from Daiichi Sankyo, other from EirGenix, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Prime/Medscape, non-financial support and other from Puma, other from Samsung, non-financial support and other from Seagen, outside the submitted work; In addition, Dr. Loibl has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending and a patent Digital Ki67 Evaluator with royalties paid. Martine Piccart-Gebhardt: Board Member (Scientific Board): Oncolytics. Consultant (honoraria): AstraZeneca, Camel-IDS, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Seattle Genetics, Immutep, Seagen, NBE Therapeutics, Frame Therapeutics. Research grants to my Institute: AstraZeneca, Immunomedics, Lilly, Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon. Speakers bureau/stock ownership: none., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Biomarkers to identify patients without benefit from adding everolimus to endocrine treatment in metastatic breast cancer (MBC) are needed. We report the results of the Pearl trial conducted in five Belgian centers assessing 18 F-FDG-PET/CT non-response (n = 45) and ctDNA detection (n = 46) after 14 days of exemestane-everolimus (EXE-EVE) to identify MBC patients who will not benefit. The metabolic non-response rate was 66.6%. Median PFS in non-responding patients (using as cut-off 25% for SUVmax decrease) was 3.1 months compared to 6.0 months in those showing response (HR: 0.77, 95% CI: 0.40-1.50, p = 0.44). The difference was significant when using a "post-hoc" cut-off of 15% (PFS 2.2 months vs 6.4 months). ctDNA detection at D14 was associated with PFS: 2.1 months vs 5.0 months (HR-2.5, 95% CI: 1.3-5.0, p = 0.012). Detection of ctDNA and/or the absence of 18 F-FDG-PET/CT response after 14 days of EXE-EVE identifies patients with a low probability of benefiting from treatment. Independent validation is needed., (© 2021. The Author(s).)

Background: HER2-positive (HER2+) breast cancer represents a heterogeneous breast cancer subtype, including both oestrogen receptor (ER) positive and negative tumours. A deeper understanding of the crosstalk between ER and HER2 receptor pathways has led to the development of treatment strategies consisting of a simultaneous blockade of both signalling pathways, as a reasonable approach to prevent the onset of mechanisms of resistance., Methods: This review was based on the material searched on PubMed, MEDLINE and Embase databases and on conference proceedings from major oncology conferences up to 15 December 2020. The search strategy included the following keywords: 'HER2-positive breast cancer', 'CDK4-6 inhibitors' and 'PI3K inhibitors', and was adapted for use with different bibliographic databases., Results: CDK4/6 and PI3K inhibitors are two classes of agents already approved in patients with hormone receptor positive, HER2-negative breast cancer. Recently, promising data with their use have been also shown in HER2+ disease. Results from preclinical and clinical studies are shedding light on the role of these classes of agents in HER2+ breast cancer, and are paving the road for a forthcoming change in clinical practice., Conclusions: Treatment landscape for HER2+ breast cancer is rapidly changing, and CDK4/6 and PI3K inhibitors represent a new promising strategy to improve patients' outcomes., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Despite the international endorsement of multidisciplinary tumor boards (MTBs) for breast cancer care, implementation is suboptimal worldwide, and evidence regarding their effectiveness in developing countries is lacking. We assessed the impact on survival and the cost-effectiveness of implementing an MTB in Mozambique, sub-Saharan Africa., Materials and Methods: This prospective cohort study included 205 patients with breast cancer diagnosed between January 2015 and August 2017 (98 before and 107 after MTB implementation), followed to November 2019. Pre- and post-MTB implementation subcohorts were compared for clinical characteristics, treatments, and overall survival. We used hazard ratios and 95% confidence intervals (CI), computed by Cox proportional hazards regression. The impact of MTB implementation on the cost per quality-adjusted life year (QALY) was estimated from the provider perspective., Results: We found no significant differences between pre- and post-MTB subcohorts regarding clinical characteristics or treatments received. Among patients with early breast cancer (stage 0-III; n = 163), the 3-year overall survival was 48.0% (95% CI, 35.9-59.1) in the pre-MTB and 73.0% (95% CI, 61.3-81.6) in the post-MTB subcohort; adjusted hazard ratio, 0.47 (95% CI, 0.27-0.81). The absolute 3-year mean cost increase was $119.83 per patient, and the incremental cost-effectiveness ratio was $802.96 per QALY, corresponding to 1.6 times the gross domestic product of Mozambique., Conclusion: The implementation of a MTB in Mozambique led to a 53% mortality decrease among patients with early breast cancer, and it was cost-effective. These findings highlight the feasibility of implementing this strategy and the need for scaling-up MTBs in developing countries, as a way to improve patient outcomes., Implications for Practice: Currently, more than half of the deaths from breast cancer in the world occur in developing countries. Strategies that optimize care and that are adjusted for available resources are needed to improve the outcomes of patients with breast cancer in these regions. The discussion of cases at multidisciplinary tumor boards (MTBs) may improve survival outcomes, but implementation is suboptimal worldwide, and evidence regarding their effectiveness in developing countries is lacking. This study evaluated the impact of implementing an MTB on the care and survival of patients with breast cancer in Mozambique, sub-Saharan Africa and its cost-effectiveness in this low-income setting., (© 2020 AlphaMed Press.)

Aim: To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial., Patients and Methods: 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac)., Results: At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74-1.00) for L+T versus T and 0.93 (95% CI, 0.81-1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T versus T and 0.88 (95% CI, 0.71-1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS% = 83% versus79%)] subgroups., Conclusion: T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer., Trial Registration: clinicaltrials.gov Identifier NCT00490139., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships that may be considered as potential competing interests:, (Copyright © 2021 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: 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.)

Background: High-throughput sequencing technologies are increasingly used in research but limited data are available on the feasibility and value of these when routinely adopted in clinical practice., Material and Methods: We analyzed all consecutive cancer patients for whom genomic testing by a 48-gene next-generation sequencing (NGS) panel (Truseq Amplicon Cancer Panel, Illumina) was requested as part of standard care in one of the largest Belgian cancer networks between 2014 and 2019. Feasibility of NGS was assessed in all study patients, while the impact of NGS on the decision making was analyzed in the group of gastrointestinal cancer patients., Results: Tumor samples from 1064 patients with varying tumor types were tested, the number of NGS requests increasing over time ( p  < .0001). Success rate and median turnaround time were 91.4% and 12.5 days, respectively, both significantly decreasing over time ( p  ≤ .0002). Non-surgical sampling procedure (OR 7.97, p  < .0001), tissue from metastatic site (OR 2.35, p  = .0006) and more recent year of testing (OR 1.79, p  = .0258) were independently associated with NGS failure. Excluding well-known actionable or clinically relevant mutations which are recommended by international guidelines and commonly tested by targeted sequencing, 57/279 (20.4%) assessable gastrointestinal cancer patients were found to have tumors harboring at least one actionable altered gene according to the OncoKB database. NGS results, however, had a direct impact on management decisions by the treating physician in only 3 cases (1.1%)., Conclusions: Our findings confirm that NGS is feasible in the clinical setting with acceptably low failure rates and rapid turnaround time. In gastrointestinal cancers, however, NGS-based multiple-gene testing adds very little to standard targeted sequencing, and in routine practice the clinical impact of NGS panels including genes which are not routinely recommended by international guidelines remains limited.

Background: Although data from preclinical and clinical studies provide a strong rationale for combining capecitabine with anti-angiogenic agents, clinical development of this fluoropyrimidine in combination with aflibercept has lagged behind other treatments. We conducted a nonrandomized, noncomparative, 2-arm, phase I trial to address this unmet need., Patients and Methods: Patients with chemorefractory gastrointestinal and breast cancer were sequentially recruited into a continuous (Arm A, starting dose 1100 mg/m 2 /day) or intermittent (Arm B, 2 weeks on/1 week off, starting dose 1700 mg/m 2 /day) capecitabine dosing arm. Aflibercept was administered at a flat dose of 6 mg/kg every 3 weeks in both arms. A classical 3 + 3, dose-escalation design was used. The primary objective was to establish the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended dose for phase II trials., Results: Thirty-eight eligible patients were recruited of whom 33 were assessable for DLTs (15 in arm A and 18 in arm B). Fourteen had colorectal cancer, 8 gastric cancer, and 11 breast cancer. DLTs included grade 2 hand-foot syndrome, grade 2 anorexia considered unacceptable by the patient, and grade 3 hypertension. The recommended dose for phase II trials for capecitabine was established at 1300 mg/m 2 /day in Arm A and 2500 mg/m 2 /day in Arm B with treatment-related grade ≥ 3 adverse events occurring in 47% and 50% of patients, respectively. Among 26 assessable patients, the objective response rate was 15.4% in Arm A and 7.7% in Arm B., Conclusion: Combining capecitabine with aflibercept is feasible and associated with a manageable safety profile and some anti-tumor activity in patients with chemorefractory gastrointestinal and breast cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Trastuzumab-associated cardiotoxicity remains an issue for patients with HER2-positive breast cancer. This pooled analysis of 3 adjuvant trials investigated the incidence, timing, impact on treatment completion, and risk factors for trastuzumab-associated cardiotoxicity., Methods: This is an individual patient data level pooled analysis of HERA, NSBAP B-31, and NCCTG 9831 (Alliance Trials). Definitions of cardiac events were as per each individual study., Results: A total of 7445 patients enrolled in the 3 trials were included in the analysis, of which 4017 were in the trastuzumab and 3428 in the control (observation) arms, respectively. Median follow-up exceeded 10 years (119.2-137.2 months). Nearly all patients (97.4%) in the trastuzumab arms received anthracycline-based chemotherapy. In total, 452 patients in the trastuzumab arms experienced a cardiac event (11.3%), with most being mildly symptomatic or asymptomatic left ventricular ejection fraction (LVEF) decrease (351 patients, 8.7%). Severe congestive heart failure was more common in the trastuzumab arm (2.3%) than in the control arm (0.8%). Most cardiac events occurred during trastuzumab treatment (78.1%) and cardiac events were the main cause of discontinuation across the sample (10.0%); nevertheless, a large majority of patients completed trastuzumab treatment (76.2%). Baseline risk factors that were significantly associated with the development of cardiac events were baseline LVEF < 60%, hypertension, body mass index > 25, age ≥ 60 and, non-Caucasian ethnicity., Conclusion: One year of trastuzumab increases the risk of cardiac events, though most consist of asymptomatic or mildly symptomatic LVEF drops. Adjuvant trastuzumab should be considered a safe treatment from a cardiac standpoint for most patients. Trastuzumab-associated cardiotoxicity is the main cause of discontinuation and further research is needed to individualize prevention and management.

Background: Lapatinib (L) plus trastuzumab (T) with weekly paclitaxel significantly increased the pathologic complete response (pCR) rate compared with the anti-human epidermal growth factor receptor 2 (HER2) agent alone plus paclitaxel. The event-free survival (EFS) and overall survival (OS) by the treatment arms L + T vs. T and L vs. T and the relationship between pCR and EFS/OS both in the whole study population and according to hormone receptor-negative and hormone receptor-positive cohorts after a median follow-up of 6.7 years were assessed., Patients and Methods: Four hundred fifty-five patients with HER2-positive early breast cancer randomly received L 1500 mg/day (n = 154), T (common dose, n = 149) or L 1000 mg/day plus T (n = 152) for 6 weeks, followed by the assigned anti-HER2 treatment combined with paclitaxel weekly × 12. After surgery, patients received 3 cycles of fluorouracil, epirubicin and cyclophosphamide. The primary end-point was pCR (ypT0/is; for current analysis, it is ypT0/is ypN0), and the secondary end-points were EFS and OS., Results: Six-year EFS rates were 67%, 67% and 74% with L, T and L + T, respectively (L vs T: hazard ratio [HR], 0.98 [95% confidence interval {CI}, 0.64-1.51; P = .93]; L + T vs T: HR, 0.81 [95% CI, 0.52-1.26; P = .35]). Six-Year OS rates were 82%, 79% and 85% for L, T and L + T, respectively (L vs T: HR, 0.85 [95% CI, 0.49-1.46; P = .56]; L + T vs T: HR, 0.72 [95% CI, 0.41-1.27; P = .26]). In landmark analyses, patients with a pCR had a significantly higher 6-year EFS (77% and 65%) and OS (89% and 77%) compared with those without a pCR for both overall and the hormone receptor-negative cohort., Conclusion: Achieving a pCR is important in HER2-positive disease and translates into better long-term outcome with regard to EFS and OS., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Tumor-infiltrating B-cells (TIL-B) in breast cancer (BC) have previously been associated with improved clinical outcomes; however, their role(s) in tumor immunity is not currently well known. This study confirms and extends the correlation between higher TIL-B densities and positive outcomes through an analysis of HER2-positive and triple-negative BC patients from the BIG 02-98 clinical trial (10yr mean follow-up). Fresh tissue analyses identify an increase in TIL-B density in untreated primary BC compared to normal breast tissues, which is associated with global, CD4+ and CD8+ TIL, higher tumor grades, higher proliferation and hormone receptor negativity. All B-cell differentiation stages are detectable but significant increases in memory TIL-B are consistently present. BC with higher infiltrates are specifically characterized by germinal center TIL-B, which in turn are correlated with TFH TIL and antibody-secreting TIL-B principally located in tertiary lymphoid structures. Some TIL-B also interact directly with tumor cells. Functional analyses reveal TIL-B are responsive to BCR stimulation ex vivo, express activation markers and produce cytokines and immunoglobulins despite reduced expression of the antigen-presenting molecules HLA-DR and CD40. Overall, these data support the concept that ongoing humoral immune responses are generated by TIL-B and help to generate effective anti-tumor immunity at the tumor site.

This study investigated the prevalence of TIL subpopulations, TLS, PD-1 and PD-L1 in tumors from TNBC patients harboring wild-type or mutated BRCA1 or BRCA2 germline genes. This TNBC cohort included 85% TIL-positive (≥10%) tumors with 21% classified as TIL hi (≥50%). Interestingly, the BRCA mut group had a significantly higher incidence of TIL pos tumors compared to the BRCA wt group (P = 0.037). T cells were dominant in the infiltrate but no statistically significant differences were detected between BRCA wt and BRCA mut for CD3 + , CD4 + and CD8 + T cells or CD20 + B cells. TLS were detected in 74% of tumors but again no significant differences between the BRCA groups. PD-1 expression was observed in 33% and PD-L1 in 53% (any cell, cut-off ≥1%) tumors for the entire TNBC cohort. PD-1 expression correlated with PD-L1 and both with TIL and TLS but was not associated with BRCA mutational status. Our analyses reveal that BRCA wt and BRCA mut TNBC are similar except for a significant increase of TIL pos tumors in the BRCA mut group. While BRCA gene mutations may not directly drive immune infiltration, the greater number of TIL pos tumors could signal greater immunogenicity in this group., (Copyright © 2019. Published by Elsevier B.V.)

Background: Although frequently used as a primary endpoint, disease-free survival has not been validated as a surrogate for overall survival in early breast cancer. We investigated this surrogacy in the adjuvant setting of treatment with anti-HER2 antibodies., Methods: In a systematic review and meta-analysis, we identified published and non-published randomised controlled trials with completed accrual and available disease-free survival and overall survival results for the intention-to-treat population as of September 2016. Bibliographic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials), clinical trial registries (Clinicaltrials.gov, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform, and PharmNet.Bund), and trial registries from relevant pharmaceutical companies were searched. Eligibility for treatment of HER2-positive early breast cancer required at least one group to have an anti-HER antibody treatment (ie, trastuzumab, pertuzumab, or trastuzumab emtansine) planned for 12 months, and at least one control arm with chemotherapy without the antibody, a lower total dose or duration of the antibody, or observation alone. Units of analysis were contrasts: two-group trials gave rise to one contrast, whereas trials with more than two groups gave rise to more than one contrast. We excluded trials enrolling patients with recurrent, metastatic, or non-invasive disease, and those testing neoadjuvant therapy exclusively. Our primary objective was to estimate patient-level and trial-level correlations between disease-free survival and overall survival. We measured the association between disease-free survival and overall survival using Spearman's correlation coefficient (r s ), and the association between hazard ratios (HRs) for disease-free survival and overall survival using R 2 . We computed the surrogate threshold effect, the maximum HR for disease-free survival that statistically predicts an HR for overall survival less than 1·00 in a future trial., Findings: Eight trials (n=21 480 patients) gave rise to a full set (12 contrasts). Patient-level associations between disease-free and overall survival were strong (r s =0·90 [95% CI 0·89-0·90]). Trial-level associations gave rise to values of R 2 of 0·75 (95% CI 0·50-1·00) for the full set. Subgroups defined by nodal status and hormone receptor status yielded qualitatively similar results. Depending on the expected number of deaths in a future trial, the surrogate threshold effects ranged from 0·56 to 0·81, based on the full set., Interpretation: These findings suggest that it is appropriate to continue to use disease-free survival as a surrogate for overall survival in trials in HER-2-positive, early breast cancer. The key limitation of this study is the dependence of its results on the trials included and on the existence of an outlying trial., Funding: Roche Pharma AG., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Limited data exist on the safety of using anti-human epidermal growth factor receptor 2 (HER2) targeted agents during pregnancy. To date, only retrospective studies have assessed the prognosis of patients with a pregnancy after prior early breast cancer, with no data in HER2-positive patients., Methods: The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial were randomized phase 3 trials for patients with HER2-positive early breast cancer. In both trials, pregnancy information was prospectively collected. Pregnancy outcomes were compared between patients unintentionally exposed to trastuzumab and/or lapatinib during gestation (the exposed group) and those who became pregnant after trastuzumab and/or lapatinib completion (the unexposed group). In the ALTTO trial, disease-free survival (DFS) was compared between pregnant patients and those aged 40 years or younger without a subsequent pregnancy via an extended Cox model with time-varying covariates to account for a guarantee-time bias., Results: Ninety-two patients (12 in the exposed group and 80 in the unexposed group) had a pregnancy: 7 in the NeoALTTO trial and 85 in the ALTTO trial. Seven patients (58.3%) in the exposed group and 10 patients (12.5%) in the unexposed group opted for an induced abortion; in the unexposed group, 10 patients (12.5%) had a spontaneous abortion. No pregnancy/delivery complications were reported for the remaining cases, who successfully completed their pregnancy, with the exception of 1 fetus with trisomy 21 (Down syndrome). No significant difference in DFS (adjusted hazard ratio, 1.12; 95% confidence interval, 0.52-2.42) was observed between young patients with a pregnancy (n = 85) and young patients without a pregnancy (n = 1307)., Conclusions: For patients with HER2-positive early breast cancer, having a pregnancy after treatment completion appears to be safe without compromising fetal outcome or maternal prognosis., (© 2018 American Cancer Society.)

Purpose: Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years., Patients and Methods: BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported., Results: Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up., Conclusion: Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.

Background: FOXP1, a transcriptional regulator of lymphocyte development, is abnormally expressed in some human tumors. This study investigated FOXP1-mediated regulation of tumor infiltrating lymphocytes (TIL) in untreated primary breast cancer (BC)., Methods: FOXP1 expression was analyzed in tissues from primary untreated breast tumors, BC cell lines and the METABRIC gene expression BC dataset. Cytokine and chemokine expression and lymphocyte migration in response to primary tumor supernatants (SN) was compared between FOXP1 hi and FOXP1 lo primary BC., Finding: FOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1 hi tumors were significantly associated with lower TIL and fewer tertiary lymphoid structures (TLS) compared to FOXP1 lo BC. Silencing FOXP1 in BC cell lines positively impacted cytokine and chemokine expression with the inverse effect associated with overexpression. CXCL9, CXCL10, CXCL11, CXCL13, CX3CL, CCL20, IL2, IL21, GZMB and IFNG expression decreased while IL10 and TGFβ increased in FOXP1 hi compared to FOXP1 lo primary BC. Lymphocyte migration using primary BC supernatants detected decreased mobility toward FOXP1 hi supernatants. FOXP1 lo BC expresses higher levels of chemokines driving TIL migration. The METABRIC gene expression dataset analysis show FOXP1 expression is associated with unfavorable BC outcomes., Interpretation: These data identify FOXP1 as an important negative regulator of immune responses in BC via its regulation of cytokine and chemokine expression. FUND: Belgian Fund for Scientific Research (FNRS 3.4513.12F) and Opération Télévie (7.4636.13F and 7.4609.15F), Fonds J.C. Heuson and Fonds Lambeau-Marteaux., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The number of breast cancer (BC) cases is growing worldwide, being most frequently diagnosed in the early-setting. Mammaprint™ is a 70-gene-expression signature, originally designed for selecting early BC patients with low risk of developing metastasis, so that they could be spared adjuvant chemotherapy. Its use as a prognostic biomarker has been extensively validated, both retrospectively and prospectively. However, its value as a predictive tool and as a clinically useful tool remains controversial. This review will describe how the test works, its application in the clinic and its limitations. Cost-effectiveness studies will be summarized. Finally, we will provide a perspective on the use of Mammaprint in the near future, as a valuable tool for personalizing the treatment of early BC patients.

Importance: Dual anti-HER2 blockade increased the rate of pathologic complete response (pCR) in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) trial, and high immune gene expression was associated with pCR in all treatment arms. So far, no marker has been identified that is specifically associated with the benefit from dual HER2 blockade., Objective: To examine if use of the T-cell β chain variable genes adds to the potential association of immune gene signatures with response to dual HER2 blockade., Design, Setting, and Participants: In the NeoALTTO trial, HER2-positive patients recruited between January 5, 2008, and May 27, 2010, were treated with paclitaxel plus either lapatinib or trastuzumab or both as neoadjuvant therapy. In this study, RNA sequencing data from baseline tumor specimens of 245 patients in the NeoALTTO trial were analyzed and reads were aligned to TRBV gene reference sequences using a previously published Basic Local Alignment Search Tool T-cell receptor mapping pipeline. Total TRBV gene use, Shannon entropy, and gene richness were calculated for each tumor, and nonnegative matrix factorization was used to define TRBV co-use metagenes (TMGs). The association between TRBV metrics, tumor genomic metrics, and response was assessed with multivariable logistic regression. Statistical analysis was performed from January 23 to December 2, 2017., Main Outcomes and Measures: The association between TRBV use metrics and pCR., Results: Among the 245 women with available data (mean [SD] age, 49 [11] years), total TRBV use correlated positively with a gene expression signature for immune activity (Spearman ρ = 0.93; P < .001). High use of TRBV11-3 and TMG2, characterized by high use of TRBV4.3, TRBV6.3, and TRBV7.2, was associated with a higher rate of pCR to dual HER2-targeted therapy (TRBV11-3 interaction: odds ratio, 2.63 [95% CI, 1.22-6.47]; P = .02; TMG2 interaction: odds ratio, 3.39 [95% CI, 1.57-8.27]; P = .004). Immune-rich cancers with high TMG2 levels (n = 92) had significantly better response to dual HER2-targeted treatment compared with the single therapy arms (rate of pCR, 68% [95% CI, 52%-83%] vs 21% [95% CI, 10%-31%]; P < .001), whereas those with low TMG2 levels did not benefit from dual therapy. High TMG2 levels were also associated with a higher rate of pCR to the combined therapy in immune-poor tumors (n = 30; pCR, 50% [95% CI, 22%-78%] vs 6% [95% CI, 0%-16%]; P = .009)., Conclusions and Relevance: Use patterns of TRBV genes potentially provide information about the association with response to dual HER2 blockade beyond immune gene signatures. High use of TRBV11.3 or TRBV4.3, TRBV6.3, and TRBV7.2 identifies patients who have a better response to dual HER2 targeted therapy., Trial Registration: ClinicalTrials.gov Identifier: NCT00553358.