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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.

Background: The erythropoietin (EPO) receptor activation can stimulate tumor proliferation and may be implicated in resistance to anti-HER2 therapies. EPO administration can be used for the management of chemotherapy-induced anemia. We aim to assess if EPO intake during the adjuvant anti-HER2 treatment impacts the outcomes of HER2-positive early breast cancer (EBC) patients. Methods: For this post hoc analysis of the ALTTO trial (NCT00490139), we categorized two cohorts according to the use of EPO during adjuvant anti-HER2 treatment: i) at least one EPO dose (EPO-cohort) vs ii) no EPO (non-EPO-cohort). We compared their baseline characteristics to identify potential confounders. The primary endpoint disease-free-survival (DFS), and the secondary endpoint overall survival (OS) were compared between these two cohorts, with subgroup analysis according to menopausal status, tumor characteristics, and anti-HER2 treatment. Kaplan Meier method, log-rank test, and Cox regression model adjusted for confounders were performed for DFS and OS (removal criterion p2 cm (56.9%), positive nodal status (58.5%), positive hormone receptor (HR) status (61.8%), and poorly differentiated or undifferentiated histologic grade (64.2%). Baseline characteristics were similar in both cohorts, except for the timing of chemotherapy, for which 93.5% of patients from the EPO-cohort were enrolled in the concurrent designs (2/2B) vs 44.2% in the non-EPO-cohort (p Citation Format: Diogo Martins-Branco, Marie Kassapian, Véronique Debien, Rafael Caparica, Daniel Eiger, Urania Dafni, Charitini Andriakopoulou, Sarra El-Abed, Miguel Izquierdo, Malou Vicente, Saranya Chumsri, Martine Piccart-Gebhart, Alvaro Moreno-Aspitia, Ann Søegaard Knop, Janine Lombard, Evandro de Azambuja. The impact of erythropoietin administration concomitantly with adjuvant anti-HER2 treatment on the patients’ outcome: Sub-analysis of the ALTTO study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-14-05.

Clinical trials cooperation is not a luxury; it is a necessity, now more than ever, first in light of the segmentation of tumors according to their molecular targets—which are being matched to an increasing number of competitive drugs—and second because it is the only chance to maintain academic research centered on addressing patients’ needs. In its 21 years of existence, the Breast International Group, an umbrella organization supporting the activities of 54 member groups across six continents, has been confronted with challenges that include (1) keeping trust and motivation within the network; (2) improving the interface between academia and industry; (3) improving patient involvement and trust in clinical trials; and (4) fundraising for noncommercial research. We describe how these challenges have been addressed so far, with the hope of empowering the next generation of clinical investigators.

Background: The number of people living with HIV is increasing worldwide thanks to the use of effective antiretroviral therapy. As these individuals get older, their risk of being diagnosed with cancer increases, including non-AIDS defining cancers such as breast cancer (BC). Most reports reveal that HIV+ patients (pts) with BC tend to be younger than HIV-uninfected (HIV-) pts. However, epidemiological data is yet conflicting regarding tumor stage at diagnosis, distribution of BC subtypes and overall survival (OS) of HIV+ pts as compared to HIV- pts. This meta-analysis aims to assess differences of baseline clinicopathological characteristics and OS of HIV+ vs HIV- BC pts. Methods: We performed a systematic review using MEDLINE, Scielo, and conference abstracts up to June 10, 2019, with no language restrictions. Cohort studies and consecutive series comparing baseline characteristics (age, stage at diagnosis or BC subtypes) and/or OS of HIV+ vs HIV- BC pts were included. BC subtypes were defined according to 2 classifications: 1) “classic” immunohistochemical (IHC) subtypes (ER+/HER2-; HER2+; triple-negative BC); 2) surrogate intrinsic subtypes as per the St. Gallen Consensus (luminal A-like, luminal B-like, HER2-enriched and basal-like). Summary risk estimates (pooled mean ratios [pMR] and odds ratios [pOR]) and 95% confidence intervals (CI) were calculated using random effects models. OS data were pooled as hazard ratios (HR) and 95% CI and modeled using a random effects model. The main endpoints were age (as a continuous variable), stage at diagnosis (early [0-II] vs late [III-IV]), distribution of BC subtypes and OS (using both adjusted and unadjusted HR). Subgroup analysis of each endpoint was performed according to region of the world. Results: A total of 16 studies (4 from North America and 12 from Sub-Saharan Africa [SSA]) published from 2005-2019 were included in this meta-analysis (with 1,764 HIV+ and 1,330,122 HIV- pts). HIV+ pts were younger than HIV- pts (pooled mean age of 41.1 vs 50.5 years, respectively; pMR 0.82, 95% CI 0.76-0.90, p < 0.001) and had a 45% increased risk of presenting with late stage disease (pOR 1.45, 95% CI 1.25-1.68, p < 0.001). There were no differences regarding distribution of BC subtypes, both by the “classic” IHC or by the St. Gallen classification. Overall, HIV+ pts had a 91% increased risk of dying as compared to HIV- pts (adjusted HR for OS: 1.91, 95% CI 1.06-3.45, p = 0.031 and unadjusted HR for OS: HR 1.47, 95% CI 1.10-1.95, p = 0.008). Subgroup analysis of OS according to region of the world showed that, in North America, HIV+ pts had a significantly increased risk of dying as compared to HIV- pts (adjusted HR 2.96, 95% CI 1.06-8.25, p = 0.038). In SSA, the increased mortality risk among HIV+ pts was also significant (adjusted HR 1.59, 95% CI 1.26-2.00, p < 0.001). Sensitivity analysis showed similar findings. Conclusion: This meta-analysis provides for the first time a comprehensive comparison of baseline characteristics and survival outcomes between HIV+ vs HIV- BC pts. Our results consistently demonstrate that HIV+ pts are diagnosed with BC at a younger age and at a more advanced stage. Additionally, even after adjusting for known prognostic factors, HIV+ pts have a worse OS as compared to HIV- pts, not only in developing countries (SSA) but also and particularly in developed countries (North America). There were no apparent differences in terms of distribution of BC subtypes. These results should raise the awareness of clinicians and policy makers regarding the detection and survival gap among HIV+ BC pts. This underserved population should be the focus of more research efforts, in order to better understand the reasons behind these disparities, which can be related to the HIV infection itself, to a more aggressive BC biology, and/or to a lower access to timely diagnosis and effective treatment. Citation Format: Mariana Brandão, Marco Bruzzone, Maria Alice Franzoi, Claudia De Angelis, Daniel Eiger, Rafael Caparica, Martine Piccart-Gebhart, Laurence Buisseret, Marcello Ceppi, Evandro de Azambuja, Matteo Lambertini. Characteristics and survival outcomes of HIV-positive breast cancer patients: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-11-03.

Background: The combination of everolimus and an endocrine agent has shown a progression-free survival (PFS) benefit but also significant toxicity in locally advanced and/or metastatic breast cancer (MBC) patients. Disappointingly, all translational research efforts conducted so far on primary/metastatic tissue or baseline ctDNA samples have failed to identify clinically useful biomarkers of benefit with the possible exception of p4EBP1 which requires fresh metastatic biopsies (Bachelot at al, ASCO 2019). Methods: Forty-seven patients were included in the PEARL trial in six Belgian centres. All patients underwent one baseline and one “early” 18FDG-PET/CT on day 14 (blinded to the treating oncologist) after treatment initiation. Eligible patients had prior progression on NSAI and at least one measurable lesion on baseline 18FDG-PET/CT (fulfilling PERCIST). Twenty seven of the 47 patients were treated in a pilot phase aiming to characterize 18FDG-PET/CT metabolic responses 14 and 28 days after treatment initiation. Day 14 18FDG-PET/CT was selected for the second phase in which 20 more patients were included to answer the primary endpoint of the trial, namely the potential of an early FDG-PET/CT to select patients who will not derive a long-term benefit from everolimus-exemestane combination. We considered as “metabolic responders” those patients in whom at least a 25% homogenous decrease in SUVmax was seen in all their target lesions; the so called “consistent” patient-based response, here correlated to PFS. Results: Seventy-four percent of the patients had visceral metastasis, 26% were pretreated with CDK 4/6 inhibitors and 58% with at least one line of chemotherapy (28% ≥ 2 lines) for the treatment of MBC. Metabolic non-response rate on day 14 was 64%. Two patients were considered non-evaluable because they stopped everolimus 3 and 8 days before early 18FDG-PET/CT respectively. The median PFS in non-responding patients was 2.3 months compared to 6 months in those who showed a consistent metabolic response (HR-1.96, 95%CI: 0.98-3.95, p=0.05). We’ll be able to assess whether day 14 ctDNA measurements add predictive value to imaging. Conclusion: Absence of 18FDG-PET/CT metabolic response after 14 days of everolimus-exemestane combination is associated with a low probability to derive benefit from this treatment. The advanced stage of the patients included in this trial (75% visceral metastasis) and their extensive prior treatments can explain the poorer outcome seen with exemestane-everolimus compared to the Bolero2 trial. Citation Format: Andrea Gombos, Martine Piccart-Gebhart, Lieveke Ameye, Peter Vuylsteke, Patrick Neven, Vincent Richard, Francois P Duhoux, Marianne Paesmans, Michail Ignatiadis, Patrick Flamen, Géraldine Gebhart. Pearl or the use of FDG positron emission tomography imaging as an early dynamic biomarker of everolimus efficacy in advanced luminal breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-22.

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 18F-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 18F-FDG-PET/CT response after 14 days of EXE-EVE identifies patients with a low probability of benefiting from treatment. Independent validation is needed., SCOPUS: ar.j, info:eu-repo/semantics/published

Background The 16th St. Gallen International Breast Cancer Conference 2019 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Design Treatments were assessed in light of their intensity, duration and side-effects, estimating the magnitude of clinical benefit according to stage and biology of the disease. The Panel acknowledged that for many patients, the impact of adjuvant therapy or the adherence to specific guidelines may have modest impact on the risk of breast cancer recurrence or overall survival. For that reason, the Panel explicitly encouraged clinicians and patients to routinely discuss the magnitude of benefit for interventions as part of the development of the treatment plan. Results The guidelines focus on common ductal and lobular breast cancer histologies arising in generally healthy women. Special breast cancer histologies may need different considerations, as do individual patients with other substantial health considerations. The panelists' opinions reflect different interpretation of available data and expert opinion where is lack of evidence and sociocultural factors in their environment such as availability of and access to medical service, economic resources and reimbursement issues. Panelists encourage patient participation in well-designed clinical studies whenever available. Conclusions With these caveats in mind, the St. Gallen Consensus Conference seeks to provide guidance to clinicians on appropriate treatments for early-stage breast cancer and guidance for weighing the realistic tradeoffs between treatment and toxicity so that patients and clinical teams can make well-informed decisions on the basis of an honest reckoning of the magnitude of clinical benefit.

Summary 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 (rs), and the association between hazard ratios (HRs) for disease-free survival and overall survival using R2. 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 (rs=0·90 [95% CI 0·89–0·90]). Trial-level associations gave rise to values of R2 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.

Summary Background HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer. Methods We did this single-arm, multicentre, phase 1b–2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed. Findings Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6–18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9–12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7–29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3–5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3–5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2. Interpretation Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients. Funding Merck, International Breast Cancer Study Group.

Background: For patients with hormone receptor-positive (HR+) advanced breast cancer (ABC), the choice of endocrine treatment should be based on the best available evidence. However, no direct head-to-head comparison of all tested regimens is currently available. This network meta-analysis aims at providing detailed inference-based data to guide decision making on endocrine therapy for HR+ ABC patients in two different clinical scenarios: endocrine-sensitive and endocrine-resistant ABC, as defined by the ABC guidelines criteria. Methods: Phase II/III randomized clinical trials published or presented up to June 15, 2018 and comparing two or more different endocrine treatments (with or without associated targeted therapies) for HR+, HER2-negative ABC patients were included, irrespective of treatment line. Relative treatment effects were pooled as hazard ratios (HRs) and modeled in a network meta-analysis using a Bayesian framework with fixed-effects models in order to infer the best approach. The main outcomes were progression-free survival (PFS) and overall survival (OS). Four separate analyses were carried out: PFS and OS networks in both endocrine-sensitive and endocrine-resistant populations. Results: A total of 26 trials were included in this meta-analysis (N=11330 patients). In the endocrine-sensitive setting, 12 trials were included in the PFS network (N=5200 patients; 10 different regimens) and 3 trials in the OS network (N=1295; 3 regimens). In terms of PFS, the combination of Fulvestrant 500 mg (F500)+CDK4/6 inhibitors (CDKi) had a 80% probability of being the most effective treatment, followed by aromatase inhibitor (AI)+CDKi (17% chance of being the best approach). The HR for the comparison between F500+CDKi vs. AI+CDKi was 0.82 (95% credibility interval [CrI] 0.54-1.25). Regarding OS, the AI+CDKi approach had a 63% chance of being the most effective regimen, followed by F500 (36% likelihood) – the comparison between the two regimens yielded a HR of 0.93 (95% CrI 0.61-1.40). In the endocrine-resistant setting, 18 trials were included in the PFS network (N=6130; 20 regimens) and 7 in the OS network (N=2701; 10 regimens). For PFS, F500+CDKi had a 59% probability of being the most effective treatment, followed by F500+Everolimus (11% likelihood). The HR of the comparison between F500+CDKi vs. F500+Everolimus was 0.84 (95% CrI 0.57-1.25). In terms of OS, F500+FGFR inhibitors had a 29% chance of being the best treatment option, followed by AI+everolimus (24% likelihood) – the HR for the comparison of F500+FGFR inhibitors vs. AI+everolimus was 1.07 (95% CrI 0.36-3.18). Conclusion: This network meta-analysis provides for the first time a comparison of all tested treatment options for HR+ ABC patients in both endocrine-sensitive and endocrine-resistant settings. In terms of PFS, F500+CDKi appears to be the best treatment option for both disease settings. As for OS, AI+CDKi is possibly the best choice for endocrine-sensitive ABC patients. Concerning endocrine-resistant disease, F500+FGFR inhibitors may be an effective regimen which should be further studied, while AI+everolimus remains the best available option in this setting. Citation Format: Brandão M, Maurer C, Ziegelmann P, Pondé N, Ferreira AR, Martel S, Piccart-Gebhart M, Debiasi M, de Azambuja E, Lambertini M. Endocrine treatment for hormone receptor-positive advanced breast cancer patients with endocrine-sensitive or endocrine-resistant disease: A systematic review and network meta-analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-01.

The clinical utility of tumor-infiltrating lymphocytes (TIL) is actively being investigated in breast cancer (BC). It is unclear whether TIL spatial location and organization in tertiary lymphoid structures (TLS) have an impact on prognosis. Additionally, the significance of PD-1 and PD-L1 expression is being debated due to conflicting data from several studies. We hypothesize that the presence, extent and spatial location of multiple immune biomarkers, reflecting ongoing immune responses, will be consistently associated with a good prognosis in highly infiltrated BC [triple-negative (TNBC) and HER2+]. The relationship between these immune biomarkers and clinical outcome was examined in the TNBC and HER2+ cohorts of node-positive BC patients enrolled in the BIG 02-98 adjuvant phase III trial with available material for immunohistochemical (IHC) labeling (N=113 and N=136, respectively). HER2+ patients did not receive trastuzumab. Dual IHC staining was performed on full-face consecutive tissue sections. Scoring was independently performed by two pathologists, blinded to the clinical data, and included: global, intratumoral and stromal TIL and TLS, assessed on CD3/CD20 slides; the percentage and location of PD-1 and PD-L1 expression, assessed on PD-1/PD-L1 slides. TIL were considered as a categorical variable with different cut-offs used for each parameter and for each cohort (TNBC and HER2+). Invasive disease-free survival (I-DFS) and overall survival (OS) were analyzed (median follow-up: 10 years). Cox proportional hazard models were used for survival analyses. The TNBC cohort revealed an association between global TIL and outcome [adjusted hazard ratio (HR) for I-DFS: 0.27 (0.15-0.51); OS: 0.26 (0.13-0.53)]. Similar results were observed for stromal and intratumoral TIL. PD-L1 expression within TLS was an independent predictor of OS, after adjustment for tumor size and age [HR: 0.30 (0.09-0.99)]. Multivariate analysis reveals this effect was principally driven by high stromal TIL (>17.5% based on CD3/CD20 assessment) (χ2 OS: p=0.009). In contrast, no significant prognostic associations were found in the overall HER2+ cohort. However high T cell TIL were associated with improved I-DFS and OS in the ER-/HER2+ group [I-DFS: 0.34 (0.14-0.80); OS: 0.32 (0.12-0.86)] and stromal TIL were associated with improved I-DFS in the ER+/HER2+ group [HR: 0.29 (0.09-0.94)] (univariate analyses). No significant associations between the number of TLS nor the expression of PD-1 with outcomes were observed in either cohorts. The presence of PD-L1+ TLS, driven by high baseline TIL, was associated with an excellent prognosis in node-positive TNBC. This observation might reflect specific immune activities taking place in these mini lymph node-like structures adjacent to the tumor bed where specific antitumor memory immune responses could be generated. No different prognostic impact was observed when analyzing TIL spatial location. Although the statistical power of the study might be limited, in line with previous findings our data reveal that, among the immune parameters evaluated, TIL are the strongest predictor of outcome in TNBC, while PD-L1+ TLS could be a new and important parameter that requires further investigation. Citation Format: Solinas C, de Wind A, Van den Eynden G, Ameye L, Garaud S, De Silva P, Boisson A, Noel G, Langouo Fontsa M, Buisseret L, de Azambuja E, Francis PA, Di Leo A, Crown JP, Sotiriou C, Larsimont D, Paesmans M, Piccart-Gebhart M, Willard-Gallo K. Immune parameters associated with survival in triple negative and HER2-positive breast cancer patients with 10 years of follow-up [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-09.

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.

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 FOXP1hi and FOXP1lo primary BC. Finding: FOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1hi tumors were significantly associated with lower TIL and fewer tertiary lymphoid structures (TLS) compared to FOXP1lo 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 FOXP1hi compared to FOXP1lo primary BC. Lymphocyte migration using primary BC supernatants detected decreased mobility toward FOXP1hi supernatants. FOXP1lo 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., SCOPUS: ar.j, info:eu-repo/semantics/published

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. The Calouste Gulbenkian Foundation supported the training of professionals (J.C., A.J., A.G.) in breast cancer care at the Centro Hospitalar Universitário de São João, under the Project “Atenção Integrada ao Doente Oncológico.” We posthumously thank Dr. João Fumane, former head of the Oncology Unit (2000–2011) and Director of the Maputo Central Hospital (from 2012 until his death, in 2017), for his continuous support to this cohort study. We thank Dr. Samantha Morais, from the Instituto de Saúde Pública, Universidade do Porto, for proof-reading the manuscript. This study was approved by the National Health Bioethical Committee of Mozambique (reference number 226/CNBS/15). All participants provided written informed consent. This study was performed in accordance with the Declaration of Helsinki. The Moza-BC cohort study was supported by the Beginning Investigator Grant for Catalytic Research (BIG Cat) program, an African Organisation for Research and Training in Cancer program with support from the U.S. National Cancer Institute (grant number 59–210–6-004). The funding source had no role in the study design, in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

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.

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.

Background HER2-positive (HER2+) breast cancer represents a heterogeneous breast cancer subtype, including both estrogen 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 signaling 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 December 15, 2020. The search strategy included the following keywords: 'HER2-positive breast cancer', 'CDK 4-6 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.

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 .

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.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.Tumor samples from 1064 patients with varying tumor types were tested, the number of NGS requests increasing over time (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/m2/day) or intermittent (Arm B, 2 weeks on/1 week off, starting dose 1700 mg/m2/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/m2/day in Arm A and 2500 mg/m2/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.

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.

Background: Dual anti-HER2 blockade resulted in increased pathologic complete response rate (pCR) in the 3 arm NeoALTTO trial. High immune gene expression and the absence of PIK3CA pathway mutations are predictive of pCR in all treatment arms but no markers were identified that could predict which patients require dual HER2 targeted therapy. The goal of this analysis was to examine if TRBV expression could add to the predictive function of previously identified immune markers. Patients and Methods: We analyzed RNA and Whole Exome sequencing data from 245 cancers (54% of all patients) included in the trial. The TRBV reference sequences were obtained from the International ImMunoGeneTics information system. Reads were aligned using a custom BLAST mapping pipeline and normalized by the total number of aligned reads in each sample. We calculated 3 T cell receptor metrics for each tumor including (i) total TRBV chain expression level, (ii) Shannon entropy of the normalized unique TRBV-expression frequencies which reflect TCR diversity and (iii) we also used non-negative matrix factorization (NMF) to define TRBV co-expression metagenes (TRBVMG). We evaluated correlation between these metrics and immune and proliferation gene expression signatures and genomic features of the cancer including clonal heterogeneity and mutation load. We assessed association between TRBV and pCR using multivariate logistic regression. Results: 65 distinct TRBV variants showed heterogeneous expression levels across cancers with strong co-expression patterns. Total TRBV expression correlated strongly with immune metagene expression (Spearman's ρ=0.93, P Conclusions: TRBV expression pattern can provide predictive information beyond known immune gene expression signatures. High expression of TRBV4.3, TRBV6.3 and TRBV7.2 variants is associated with higher pCR rate with dual HER2 targeted and paclitaxel neoadjuvant therapy. Citation Format: Powles R, Redmond D, Sotiriou C, Loi S, Fumagalli D, Nuciforo P, Harbeck N, de Azambuja E, Sarp S, Di Cosimo S, Huober J, Baselga J, Piccart-Gebhart M, Elemento O, Hatzis C, Pusztai L. T-cell receptor beta chain variable region (TRBV) expression patterns predict response to combined trastuzumab/lapatinib treatment in the NeoALTTO/BIG-1-06 trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-01.

To determine the value of mammography and breast ultrasound (US) in predicting outcomes in HER2 positive breast cancer patients (pts) within Neo-ALTTO trial.Mammography and US were required at baseline, week 6 and surgery. Two independent blinded investigators reviewed the measurements and assigned the corresponding response category. Pts showing complete or partial response according to RECIST (v1.1) were classified as responders. The association between imaging response at week 6 or prior to surgery was evaluated with respect to pathological complete response (pCR) and event-free Survival (EFS).Of the 455 pts enrolled in the trial, 267 (61%) and 340 (77%) had evaluable mammography and US at week 6; 248 (56%) and 309 (70%) pts had evaluable mammography and US prior to surgery. At week 6, 32% and 43% of pts were classified as responders by mammography and US, respectively. pCR rates were twice as high for responders than non-responders (week 6: 46% versus 23% by US, p 0.0001; 41% versus 24% by mammography, p = 0.007). Positive and negative predictive values of mammography and US prior to surgery were 37% and 35%, and 82% and 70%, respectively. No significant correlation was found between response by mammography and/or US at week 6/surgery and EFS.Mammography and US were underused in Neo-ALTTO although US had the potential to assess early response whereas mammography to detect residual disease prior to surgery. Our data still emphasise the need for further imaging studies on pts treated with neoadjuvant HER2-targeted therapy.

Purpose Women receiving trastuzumab with chemotherapy are at risk for trastuzumab-related cardiac dysfunction (TRCD). We explored the prognostic value of cardiac markers (troponins I and T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) to predict baseline susceptibility to develop TRCD. We examined whether development of cardiac end points or significant left ventricular ejection fraction (LVEF) drop was associated with markers’ increases. Patients and Methods Cardiac marker assessments were coupled with LVEF measurements at different time points for 533 patients from the Herceptin Adjuvant (HERA) study who agreed to participate in this study. Patients with missing marker assessments were excluded, resulting in 452 evaluable patients. A primary cardiac end point was defined as symptomatic congestive heart failure of New York Heart Association class III or IV, confirmed by a cardiologist, and a significant LVEF drop, or death of definite or probable cardiac causes. A secondary cardiac end point was defined as a confirmed significant asymptomatic or mildly symptomatic LVEF drop. Results Elevated baseline troponin I (> 40 ng/L) and T (> 14 ng/L), occurring in 56 of 412 (13.6%) and 101 of 407 (24.8%) patients, respectively, were associated with an increased significant LVEF drop risk (univariate analysis: hazard ratio, 4.52; P < .001 and hazard ratio, 3.57; P < .001, respectively). Few patients had their first elevated troponin value recorded during the study (six patients for troponin I and 25 patients for troponin T). Two patients developed a primary and 31 patients a secondary cardiac end point (recovery rate of 74%, 23 of 31). For NT-proBNP, higher increases from baseline were seen in patients with significant LVEF drop. Conclusion Elevated troponin I or T before trastuzumab is associated with increased risk for TRCD. A similar conclusion for NT-proBNP could not be drawn because of the lack of a well-established elevation threshold; however, higher increases from baseline were seen in patients with TRCD compared with patients without.

Background: Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial.Methods: HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov ( NCT00045032).Findings: Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09–11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68–0·86) and death (0·74, 0·64–0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89–1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group.Interpretation: 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit.Funding: F Hoffmann-La Roche (Roche).

Background The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five yrs of adjuvant treatment with letrozole, tamoxifen, or their sequence in postmenopausal women with hormone-receptor–positive early breast cancer. The study is conducted by the International Breast Cancer Study Group (IBCSG) on behalf of BIG. 8010 patients (pts) were enrolled between March 1998 and May 2003, and first results demonstrating a significant DFS benefit favoring letrozole compared with tamoxifen were reported in 2005 at 25.8 months' MFU. Subsequent updates showed continuing DFS benefit and updated results published in 2011 at 8.1 yrs' MFU showed OS benefit. Industry-sponsorship of the original BIG 1-98 ended in 2010; IBCSG launched an observational, non-interventional long-term follow-up study (BIG 1-98 LTFU) to collect survival, disease status and adverse events for an additional 5 yrs. We report results from BIG 1-98 LTFU at 12 yrs' MFU. Methods The original trial includes the 8010 patients enrolled. The potential BIG 1-98 LTFU cohort consisted of 148 academic medical centers with a maximum of 6843 pts who were alive and continuing follow-up when the original study ended. Response bias was addressed using weighting class adjustments estimated using multivariable logistic regression. Unadjusted incidence rates are reported here per 1000 pt-yrs with 95% Poisson confidence intervals. An updated abstract will include adjusted incidence rates, as well as estimates of OS and DFS based on a weighted Kaplan-Meier approach. The database will close in July 2016. Results As of May 2016, 81 centers participated in the BIG 1-98 LTFU study, contributing data from approximately 3900 pts (57%) and extending MFU to 12 yrs. Compared with the potential cohort of 6843 pts, the ~3900 in the LTFU analytic cohort were more likely to be under age 65 yrs at enrollment, have node-positive disease, and have tumors that were < 2 cm, PgR positive (≥1%), and with no evidence of peritumoral vascular invasion. Extended adjuvant endocrine therapy for primary BC was continued in 2% of pts. Unadjusted incidence estimates of myocardial infarction increased during LTFU, while incidence of thromboembolic events and osteoporosis decreased (Table). Variations in incidence rates were noted depending on recording mechanism (e.g. registry, clinic visit, telephone, information from family). Unadjusted Incidence Rate/1000 pt-yrs (95% CI)Adverse EventDuring original studyDuring LTFUMyocardial Infarction1.7 (1.4-2.0)3.5 (2.7-4.5)Thromboembolic event6.0 (5.4-6.6)2.5 (1.8-3.3)Osteoporosis23.6 (22.5-24.9)18.2 (16.3-20.3)Bone fractures17.2 (16.2-18.3)15.0 (13.2-16.9) Overall 1845 deaths were reported; the unadjusted incidence of death was lower in the original study compared with during LTFU (21.9 vs. 26.6/1000 pt-yrs); incidence remained relatively stable for pts assigned to tamoxifen (24.9 vs. 25.2/1000 pt-yrs), and increased for pts assigned to letrozole (22.0 vs. 27.1/1000 pt-yrs). Conclusions The BIG 1-98 LTFU study has been successfully conducted. The additional data from the BIG 1-98 LTFU study provides important long-term clinical information about OS, DFS and adverse events. Citation Format: Thürlimann B, Giobbie-Hurder A, Colleoni M, Jensen M-B, Ejlertsen B, de Azambuja E, Neven P, Láng I, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Price K, Piccart-Gebhart M, Regan MM, Gelber RD, Coates AS, Goldhirsch A. 12 years' median follow up (MFU) of BIG 1-98: Adjuvant letrozole, tamoxifen and their sequence for postmenopausal women with endocrine responsive early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-05.

Background: We performed whole-exome sequencing of pretreatment biopsies and examined whether genome-wide metrics of overall mutational load, clonal heterogeneity or alterations at variant, gene, and pathway levels are associated with treatment response and survival. Patients and methods: Two hundred and three biopsies from the NeoALTTO trial were analyzed. Mutations were called with MuTect, and Strelka, using pooled normal DNA. Associations between DNA alterations and outcome were evaluated by logistic and Cox-proportional hazards regression. Results: There were no recurrent single gene mutations significantly associated with pathologic complete response (pCR), except PIK3CA [odds ratio (OR) = 0.42, P = 0.0185]. Mutations in 33 of 714 pathways were significantly associated with response, but different genes were affected in different individuals. PIK3CA was present in 23 of these pathways defining a ` trastuzumab resistance-network' of 459 genes. Cases with mutations in this network had low pCR rates to trastuzumab (2/50, 4%) compared with cases with no mutations (9/16, 56%), OR = 0.035;P< 0.001. Mutations in the ` Regulation of RhoA activity' pathway were associated with higher pCR rate to lapatinib (OR = 14.8, adjusted P = 0.001), lapatinib_trastuzumab (OR = 3.0, adjusted P = 0.09), and all arms combined (OR v 3.77, adjusted P = 0.02). Patients (n = 124) with mutations in the trastuzumab resistance network but intact RhoA pathway had 2% (1/41) pCR rate with trastuzumab alone (OR = 0.026, P = 0.001) but adding lapatinib increased pCR rate to 45% (17/38, OR = 1.68, P = 0.3). Patients (n = 46) who had no mutations in either gene set had 6% pCR rate (1/15) with lapatinib, but had the highest pCR rate, 52% (8/15) with trastuzumab alone. Conclusions: Mutations in the RhoA pathway are associated with pCR to lapatinib and mutations in a PIK3CA-related network are associated with resistance to trastuzumab. The combined mutation status of these two pathways could define patients with very low response rate to trastuzumab alone that can be augmented by adding lapatinib or substituting trastuzumab with lapatinib.

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. ispartof: JCI INSIGHT vol:4 issue:18 ispartof: location:United States status: published

Background Design, conduct, and analysis of randomized clinical trials (RCTs) with time to event end points rely on a variety of assumptions regarding event rates (hazard rates), proportionality of treatment effects (proportional hazards), and differences in intensity and type of events over time and between subgroups. Design and methods In this article, we use the experience of the recently reported Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) RCT, which enrolled 8381 patients with human epidermal growth factor 2-positive early breast cancer between June 2007 and July 2011, to highlight how routinely applied statistical assumptions can impact RCT result reporting. Results and conclusions We conclude that (i) futility stopping rules are important to protect patient safety, but stopping early for efficacy can be misleading as short-term results may not imply long-term efficacy, (ii) biologically important differences between subgroups may drive clinically different treatment effects and should be taken into account, e.g. by pre-specifying primary subgroup analyses and restricting end points to events which are known to be affected by the targeted therapies, (iii) the usual focus on the Cox model may be misleading if we do not carefully consider non-proportionality of the hazards. The results of the accelerated failure time model illustrate that giving more weight to later events (as in the log rank test) can affect conclusions, (iv) the assumption that accruing additional events will always ensure gain in power needs to be challenged. Changes in hazard rates and hazard ratios over time should be considered, and (v) required family-wise control of type 1 error ≤ 5% in clinical trials with multiple experimental arms discourages investigations designed to answer more than one question. Trial Registration clinicaltrials.gov Identifier NCT00490139.

The HER2-targeted antibody–drug conjugate trastuzumab emtansine (T-DM1) is approved for the treatment of metastatic, HER2-positive breast cancer after prior trastuzumab and taxane therapy, and has also demonstrated efficacy in the adjuvant setting in incomplete responders to neoadjuvant therapy. Despite its objective activity, intrinsic and acquired resistance to T-DM1 remains a major clinical challenge. T-DM1 mediates its activity in a number of ways, encompassing HER2 signalling blockade, Fc-mediated immune response and payload-mediated microtubule poisoning. Resistance mechanisms relating to each of these features have been demonstrated, and we outline the findings of these studies in this review. In our overview of the substantial literature on T-DM1 activity and resistance, we conclude that the T-DM1 resistance mechanisms most strongly supported by the experimental data relate to dysfunctional intracellular metabolism of the construct and subversion of DM1-mediated cell killing. Loss of dependence on signalling initiated by HER2–HER2 homodimers is not substantiated as a resistance mechanism by clinical or experimental studies, and the impact of EGFR expression and tumour immunological status requires further investigation. These findings are instructive with respect to strategies that might overcome T-DM1 resistance, including the use of second-generation anti-HER2 antibody–drug conjugates that deploy alternative linker-payload chemistries., SCOPUS: re.j, info:eu-repo/semantics/published

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. ispartof: EUROPEAN JOURNAL OF CANCER vol:118 pages:169-177 ispartof: location:England status: published

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. 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. 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 25, age ≥ 60 and, non-Caucasian ethnicity. 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.

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.