Search

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo (NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287).Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/mA total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036]; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred.Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.

BACKGROUND Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial. PATIENTS AND METHODS Left ventricular ejection fraction (LVEF) ≥ 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as ≥10% from baseline and to 65 years, body mass index ≥ 25 kg/m2, baseline LVEF between 55% and

In 2014, we described a method to quantify percentage of tumor-infiltrating lymphocytes (TILs) on hematoxylin and eosin-stained slides of breast cancer samples using light microscopy that could be performed easily by pathologists with no extra stains. The aim of detailing the method was to facilitate independent research groups replicating our prognostic findings using TIL quantity in early-stage breast cancers. A global working group of breast pathologists was convened to standardize, test reproducibility, and refine the method. A website was also established which allowed free training (www.tilsinbreastcancer.org). As a result of this work, TIL data have been collected in over 20 000 primary breast cancer samples worldwide and the robust associations with better prognoses in triple-negative breast cancer (TNBC) and HER2+ BC have been confirmed. This has resulted in the inclusion of the TIL biomarker in several international breast cancer guidelines as well as in national criteria for routine pathology reporting. TIL therefore represents the first biological prognostic biomarker for early-stage TNBCs, and here its prognostic effect is linear, with values of 30%-50% being suggested as suitable for use in potential chemotherapy de-escalation studies. The efficacy of immune checkpoint-targeted agents in breast cancer now provides direct evidence that host immune responses can modify tumor growth in some patients. With the recent granting of accelerated approvals for the first PD-1/PD-L1 targeting agents in early and advanced TNBC, our focus has now moved to investigating the clinical utility of TIL in the setting of immune checkpoint agents, with or without PD-L1 protein assessment. Emerging data suggest that TIL quantity can help clinicians identify patients with breast cancer who benefit most from PD-1/PD-L1 inhibition. In patients with advanced TNBC and HER2+ disease a TIL cut-off of 5% or 10%, with PD-L1 expression can define 'immune-enriched' tumors and currently seems to have the most clinical relevance in this context.

BACKGROUND Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment. PATIENTS AND METHODS SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5). RESULTS Intention-to-treat population included 4851 women in SOLE (n��= 2425 in the intermittent and n��= 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n��= 78 in the intermittent and n��= 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment. CONCLUSIONS Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption.

Background In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. Patients and methods KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). Results The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. Conclusions T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Sin financiación 32.976 JCR (2020) Q1, 7/242 Oncology 8.590 SJR (2021) Q1, 2/133 Hematology No data IDR 2020 UEM

In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB.HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized.Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events.With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

Introduction: In Rx ponder patients with nodal involvement and a recurrence score between 0-25 were randomised to receive either chemotherapy followed by endocrine therapy or endocrine therapy alone. Patients were stratified by recurrence score (RS) 0-13 vs 14-25, menopausal status and type of axillary surgery. 50% of the patients randomised to chemotherapy received TC (4 or 6 cycles) and ovarian function suppression (OFS) was used in 16% in the ET arm and 3% in the chemotherapy plus ET arm (CET). 33% of the patients enrolled were premenopausal. The overall analysis demonstrated that patients with CET had a significantly higher iDFS at 5 years than those with ET (92.4% vs 91%); HR 0.81, p=0.026. There was a significant interaction of menopausal status and chemotherapy. 5-year iDFS was 94.2% with CET and 89% with ET (delta 5.2%); HR 0.54; p=0.0004, which was larger in the group with a RS 13-25. Because the use of OFS in the CET arm was only 3% it was hypothesised that the main effect of chemotherapy is due to ovarian function suppression. Main Part: OFS added to tamoxifen or AI is very effective in premenopausal women as shown by the SOFT and TEXT studies. The majority of women in SOFT and TEXT received chemotherapy and the effect was observed mainly in the group receiving chemotherapy (a surrogacy for high risk). Adding OFS to tamoxifen plus chemotherapy vs chemotherapy plus tamoxifen is better. The LHRH metaanalysis demonstrated that LHRH was about equally effective to chemotherapy. However, the majority of trials used 2 years LHRH, chemotherapy consisted mainly of CMF and the effect was seen in women under 40 years. The subsequent metaanalyses by the EBCTCG support chemotherapy regardless of ET and menopausal status. Anthracycline and taxane containing chemotherapy is more effective than CMF and dose-dense chemotherapy is even more effective than standard chemotherapy. Chemotherapy can induce amenorrhoea and women with chemotherapy induced amenorrhea have a better outcome than those without. Cyclosphosphamide and especially in the CMF regimen have the highest rate of amenorrhea and the main effect is seen in women between 40 and 50 years. Younger women regain menses, so the ovarian function suppression is temporarily, especially in women below 40 years. The dose of cyclophosphamide in the TC regimen, which was predominantly used in Rx-Ponder is lower than in the CMF regimen but similar to modern type chemotherapy regimen. In RX-Ponder the chemotherapy effect was seen in all premenopausal women but there was no difference of the point estimate in women between 40-50 and younger than 40 years of age. The ovarian function suppression effect is transient and women under 40 year of age tend to regain menopause and should receive an LHRH in addition. In very young women the ovarian function suppression with an LHRH analogue is about 80% leaving 20% without adequate OFS. The toxicity rate of 5 years of LHRH containing ET is high and should not be underestimated compared to 4-6 months chemotherapy. Compliance of LHRH is lower than in adjuvant chemotherapy affecting the effectiveness of adjuvant therapy. If LHRH is discontinued at 2years of LHRH the patient will receive only tamoxifen, which is too little in high risk, premenopausal women. The recurrence score mainly measures endocrine sensitivity of the tumour which does not imply chemoresistance. Nodal status remains still the most important prognostic factor and chemotherapy reduces the risk of recurrence by 30-40%.The data from Rx-Ponder are comparable to the data generated in the Mindact trial. In women younger than 50 years being at clinical high risk but with a genomic low risk tumour chemotherapy improved 8-year DDFS to 93.6% compared to 88.6% without chemotherapy (HR 0.54 95%; CI 0.30-0.98).In conclusion: Premenopausal women with node-positive HR+/HER2- breast cancer benefit from the use of chemotherapy in addition to LHRH even if the RS indicates a biological low risk. Citation Format: S Loibl. Con - RxPONDER: Was it all OFS? [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 DEB1-2.

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.

Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC.GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0).A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P = 0.287), corresponding to OR = 1.45 (95% CI 0.80-2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06-4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased pCR (P 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy.ClinicalTrials.gov number: NCT02685059.

Background: We have previously shown that expression of the IL8/VEGFA-metagene eliminates the good prognostic effect of TILs in TNBC (PMID 21978456, 28750120). We also showed that the VEGFA metagene predicted response to neoadjuvant bevacizumab in the GeparQuinto trial (Karn 2017 SABCS #851166). The main cellular sources of the transcripts that comprise the VEGFA metagene are unknown since mRNA profiling of bulk biopsies contains signals from different cell types. Methods: Individual genes that comprise the VEGFA metagene were measured in bulk tissue- and single cell-RNA-Seq from breast cancer subtypes and normal cells on different platforms (Affymetrix n=4915, Agilent n=597, Illumina n=2433, RNA-Seq n=1215, Exome Capture RNA-Seq n=226, HTG-Seq n=243, sc-RNA-Seq n=24710). For blinded, orthogonal validation we performed immunohistochemistry. Effect of neoadjuvant chemotherapy with or without bevacizumab was studied by RNA-Seq and IHC on samples from GeparQuinto trial. SWOG S0800 (GSE114403), PROMIX (GSE87455), and GeparSixto trials were used for validation. TCGA was mined for mutations and somatic CNA. RNA-Seq from GeparNuevo was used for correlation with checkpoint inhibitor treatment. Results: We identified a stable core of six genes (VEGFA, ANGPTL4, ADM, NDRG1, DDIT4, CSTB) in different cohorts. Strong expression of this signature was mainly restricted to TNBC subtype and associated with poor prognosis within this subgroup. Single cell RNA-Seq of breast epithelial cells from 4 reduction mammoplasties and 4 TNBC revealed that these genes are coexpressed in individual epithelial cells and not associated with endothelial cells. In line with their presumed functions in cellular stress and hypoxia, immunohistochemistry revealed strong para-necrotic expression in TNBC. Moreover, high gene expression in TNBC was associated with mutations in DNA damage control pathways, somatic copy number alterations, and lower TILs. While chemotherapy led to downregulation, bevacizumab increased expression. In multivariate analysis, high pretreatment values predict pCR to both bevacizumab and chemotherapy (OR 2.40, P=0.006), which may be explained by sensitivity of tumors which are already under cellular stress. On the other hand, expression of the VEGFA metagene seems to create an immunosuppressive environment that counteracts the positive prognostic effect of TILs. In pre-treatment biopsies from the GeparNuevo checkpoint inhibitor trial we found a negative correlation of VEGFA metagene expression with the amount of the recently identified tissue-resident memory T cell subset (CD8TRM, PMID 29942092; P=0.002), while the subsequent increase of CD8TRM during treatment was larger in tumors with high VEGFA (P=0.019). Conclusions: Perinecrotic carcinoma cells under stress from hypoxia and or chromosomal instability are the source of the VEGFA metagene signature. Its predictive value in TNBC suggests estimating and reporting the amount of necrosis in the pathology report may be helpful in predicting response to preoperative chemotherapy, and could be used as stratification factor in clinical trials. The signature indicates an immunosuppressive environment and should be further studied in the context of immune therapies in combinations with anti-angiogenic treatment. Citation Format: Karn T, Denkert C, Sinn BV, Weber K, Nekljudova V, Rody A, Meissner T, Hatzis C, El-Balat A, Becker S, Solbach C, Untch M, Schneeweiss A, von Minckwitz G, Loibl S, Pusztai L, Holtrich U. Single-cell profiling identifies hypoxic carcinoma cells as source of an immunosuppressive VEGFA metagene [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 P3-10-01.

Purpose: Endocrine based therapy is an effective strategy to manage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, nearly all patients exhibit/develop either de novo or acquired resistance. While prognostic biomarkers of endocrine responsiveness are well established for the adjuvant treatment in ER+ breast cancer, less is known regarding prognostic and predictive biomarkers of response in the first line ABC setting. We sought to develop a clinical calculator based on clinical criteria for predicting progression-free survival (PFS) and overall survival (OS) of women with HR+/HER2- ABC who will be receiving endocrine monotherapy as first-line treatment for ABC. Methods: The development of the clinical calculator will be based on data from modern clinical trials in women with HR+/HER2- ABC. The studies to be included in the final analyses are given in Table 1. The control arm data from trials1-6 will form the training dataset (N = 1,223) and be used to construct the clinical prediction models. Variables considered include age, race, ECOG status, disease measurability, body mass index, disease-free interval, number of metastatic sites, locations of metastatic sites, prior endocrine therapy, and prior chemotherapy. Missing values will be imputed using single imputation with all variables included in the imputation model. For continuous variables, restricted cubic splines will be used to determine if non-linear effects may be more appropriate. The Lasso regression will be used as a variable selection technique to reduce the dimensionality of covariates; initially all pairwise interactions will be included in the model. Following Lasso regression, the multivariable Cox proportional hazards models will be constructed for PFS and OS including only variables retained in Lasso. The final model will be internally validated for discrimination and calibration using 10-fold cross-validation. External validation will be performed using control arm data from EGF 30008 (N = 536). Results: To date, control arm data from four trials (trials 1-4) have been received. The preliminary results presented here are based on pooled data from C40503 and LEA, for which data elements have been harmonized. Models for predicting PFS and OS have good calibration and are associated with bias-corrected C-indices of 0.61 and 0.65, respectively. These models will be updated using pooled data from trials 1-6. Conclusions: Our preliminary data demonstrate that clinical calculators based on baseline clinical factors can provide accurate prediction of PFS and OS in patients with HR+/HER2- ABC treated with first-line ET. If validated, these tools may be used for risk stratification in future clinical trials and to identify patients who may require more or less aggressive therapy. Table 1:Studies to be includedTrial NumberTrial NameTrial PISample Size in Control Arm1C40503Maura Dickler152 (letrozole)2LEAMiguel Martin179 (letrozole)3FACTJonas Bergh188 (anastrozole)4FALCONJohn Robertson194 (anastrozole)5S0226Rita Mehta345 (anastrozole)6MONARCH 3Matthew Goetz165 (nonsteroidal AI)7EGF 30008Stephen Johnston536 (letrozole) Citation Format: Polley M-YC, Dickler MN, Johnston S, Goetz MP, de la Haba J, Loibl S, Mehta RS, Bergh J, Roberston J, Barlow W, Liu H, Tenner K, Martin M. A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced stage breast cancer treated with first-line endocrine therapy [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 P2-07-05.

Background Even though patients with a pCR following neoadjuvant chemotherapy have an excellent prognosis still some of these patients will eventually relapse. A better identification of pts with an increased risk of relapse despite a pCR would be helpful to select these patients for additional post-neoadjuvant treatment strategies. Thus, the rationale of this retrospective analysis was to identify factors predicting relapse despite a pCR. Methods This pooled retrospective analysis based on the GBG meta-database includes the neoadjuvant trials GeparTrio, GeparQuattro, GeparQuinto, GeparSixto and GeparSepto. In these trials 2188 (27%) of 7933 pts had a pCR according to ypT0/ypTis ypN0 Definition and were included. The primary endpoint was disease-free survival (DFS), secondary endpoints were distant DFS (DDFS) and overall survival (OS). A multivariate Cox proportional hazards model was used to report hazard ratios with 95% confidence interval (CI). The two-sided significance level was set to α=0.05. Endpoints were analysed for all pts and in subgroups defined by intrinsic subtypes. The potential risk factors intrinsic subtype (HER2 negative/hormone receptor (HR) positive, triple negative, HER2 positive/HR positive, HER2 positive/HR negative), histological tumor type (lobular vs other), grade (G1/G2 vs G3), KI67 (≤20% vs higher), initial cT and cN stadium (cT1 vs cT2 vs cT3/4; cN0 vs cN+), age (≤40 vs 41-59 vs ≥60), BMI (< 25 vs 25-29 vs ≥ 30), planned number of cycles of chemotherapy (≤6 vs > 6), menopausal status (pre- vs postmenopausal) and clinical response after 2-4 cycles (SD vs PR vs CR vs PD) were included as covariates in multivariate Cox regression models as well as study identification. Results From 2188 evaluable patients DFS, DDFS and OS events were observed in 290/197/130 pts respectively; the median follow-up over all studies was 59 months. In multivariate analysis including study and all potential risk factors DFS was significantly different with regard to the initial cN status (cN+ vs cN0, hazard ratio (HR) 1.70; 95% CI [1.2, 2.4], p=0.002). Of borderline significance was histological type (non-lobular vs lobular, HR 0.52 95% CI [0.3, 1.1]; p=0.076) and initial tumor stage (cT3/4 vs cT1, HR 1.61 95% CI [1.0, 2.7]; p=0.064). In terms of DDFS significant differences were seen for the initial cN status (cN+ vs cN0, HR 2.34; 95% CI [1.5, 3.6], p Conclusions Initial tumor load before start of neoadjuvant chemotherapy (tumor stage and nodal status) and lobular subtype were predictors of long term outcome after a pCR following neoadjuvant chemotherapy. Intrinsic subtype, KI67, grade and planned number of cycles were not predictive for a relapse. Citation Format: Huober J, Schneeweiss A, Blohmer J-U, Denkert C, Tesch H, Hanusch CA, Salat C, Rhiem K, Rezai M, Solbach C, Fasching PA, Jackisch C, Mehta K, Nekljudova V, Seither F, von Minckwitz G, Loibl S, Untch M. Factors predicting relapse in early breast cancer patients with a pathological complete response after neoadjuvant therapy – Results of a pooled analysis based on the GBG meta-database [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 P2-08-01.

Background: The GeparNuevo trial showed a numerical increase in the pCR rate to 53% vs 44%; p=0.281 compared to placebo in TNBC with the addition of the anti-PD-L1 antibody durvalumab to a neoadjuvant anthracycline-taxane containing chemotherapy (Loibl S et al. ASCO 2018). In a predefined subgroup analysis, a significant increase of the pCR rate was observed for patients that received durvalumab for 2 weeks alone prior to the start of chemotherapy in a window phase (61% vs 41%, p interaction=0.048), while the pCR rate was not increased for the subset of patients that did start durvalumab together with chemotherapy. Here we report the main results of the translational programme for GeparNuevo with a focus on mRNA signatures predictive for pCR in pretherapeutic core biopsies. Methods: A total of 162 baseline FFPE core biopsies were evaluable for expression of 2560 genes using the HTG EdgeSeq® system that combines a modified nuclease protection assay with next generation sequencing. Data was processed as recommended by the HTG and median transformed for further analyses. For differential gene expression analyses, the data was scale-normalized (TMM normalization; EdgeR package) and linear models were fit (limma package). Prior to these analyses, genes were filtered based on minimal expression (> 4) and variability (IQR > 1). As a first step, predefined immune-genes signature (TILs signature) (Denkert et al. JCO 2016) as well as IFN-gamma signatures were evaluated for correlation with pCR in logistic regression models. Subsequently, we performed a differential gene expression analysis according to therapy response for the durvalumab-arm and the placebo arm using the pre-filtered candidate genes. Gene names are not included in this abstract to allow filing of IP, but full gene names will be presented at the SABCS meeting. Results: The predefined TIL- and IFN-gamma signatures were associated with increased pCR rates in the complete cohort (TIL-signature: OR 1.44, 95% CI 1.15-1.82, p=0.002; IFN-Gamma-signature: OR 1.63, 95% CI 1.22-2.24, p=0.002) as well as in the durvalumab arm (p=0.012 and 0.042) and the placebo arm (p=0.050 and 0.011). These signatures were general pCR predictors without specificity for durvalumab response. Additional 44 genes were significantly (p Conclusion: Our results show that specific immune-related gene expression signatures predict response to durvalumab in primary triple negative breast cancer. The trial was financially supported by Astra Zeneca and Celgene Citation Format: Loibl S, Sinn BV, Karn T, Untch M, Treue D, Sinn H-P, Weber KE, Hanusch CA, Fasching PA, Huober J, Zahm D-M, Jackisch C, Thomalla J, Blohmer J-U, Marmé F, Klauschen F, Rhiem K, Felder B, von Minckwitz G, Burchardi N, Schneeweiss A, Denkert C. mRNA signatures predict response to durvalumab therapy in triple negative breast cancer (TNBC)– Results of the translational biomarker programme of the neoadjuvant double-blind placebo controlled GeparNuevo trial [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 PD2-07.

Background: Palbociclib (PAL) in combination with endocrine therapy (ET) is a preferred treatment option for untreated and previously treated patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative ABC. Patients with bone only disease could derive prolong disease control with single agent ET. Further understanding the predictive markers for sensitivity to ET alone and P+ET in both endocrine sensitive and resistant settings could help guide clinical treatment sequencing decision. We performed biomarker (BM) analysis of baseline tumor tissues in both PALOMA-2 (P2) and PALOMA-3 (P3) in bone only (BO) vs non-bone (NBO) only patients. Methods: Postmenopausal women (N=666) with no prior systemic therapy for ER+/HER2-ABC were randomized 2:1 to receive PAL+LET or matching placebo (PBO)+LET in P2. In P3 women (N=521) who progressed on prior endocrine therapy were randomized 2:1 to receive PAL+ FUL vs matching PBO+FUL. All pts including those with BO disease had to consent to provide tumor tissues to participate the current study. EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics; Tucson, AZ) was used for mRNA profiling. Cox regression analysis was used to evaluate the association of BO disease with treatment effect as well as the association of gene expression with treatment effect in BO vs NBO pts. Results: Treatment effect in the BM population from each study was consistent with that observed in the respective ITT population. In ITT population, BO disease was reported in 151 (23%) pts of P2 with mPFS 36.2mo PAL+LET arm (n=103) vs 11.2mo LET arm (n=48), HR=0.40 (0.26-0.62) and in 124 (24%) pts of P3 with mPFS 14.3mo PAL+FUL arm (n=86) vs 9.2mo FUL arm (n=38), HR=0.64(0.38-1.06). BO disease was reported in 107 (24%) pts in P2 and 81 (27%) pts in P3 BM population. In P2, longer mPFS was seen with PAL+ LET vs PBO+LET in BO vs NBO disease (30.6 mo vs 11.2 mo; HR=0.42 (0.25-0.69) in BO pts and 22.1 mo vs 13.8 mo HR=0.67 (0.52-0.88) in NBO pts) although the interaction effect was not statistically significant. Similar results were also observed in P3 with longer mPFS in PAL+FUL vs PBO+FUL in BO vs NBO disease (16.6 mo vs 11.2 mo HR=0.79 (0.40-1.56) in BO pts and 11.1mo vs 3.5 mo HR=0.47 (0.34-0.66) in NBO pts) with insignificant interaction effect. In both studies, BO pts had higher incidence of luminal A disease (BO vs NBO: P2=62% vs 47%; P3=54% vs 40%) and lower rate of luminal B disease (P2=19% vs 33%; P3: 26% vs 33%). In both studies, baseline ESR1, Cyclin E and CDK 4 gene expression level were comparable between BO vs NBO pts. Elevated CDK4 gene expression level was associated with resistance to LET in P2 and lower Cyclin E gene expression predicts the effect of PAL in P3. Conclusion: mPFS was significantly prolonged in BO pts with the addition of PAL to ET. BO disease was more frequently associated with luminal A subtype in ABC setting. CDK4 expression level was similar to NBO disease pts but associated with resistance to single agent LET. Citation Format: Finn RS, Turner NC, Liu Y, Rugo HS, Loibl S, Diéras V, Slamon DJ, André F, Gelmon K, DeMichele A, Loi S, Zhang Z, Giorgetti C, Gauthier E, Huang Bartlett C, Cristofanilli M. Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies [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 P6-18-03.

Background: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway can occur due to PIK3CA mutations, present in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2—) ABC. SOLAR-1, a Phase 3 randomized, double-blind trial (NCT02437318), investigated efficacy and safety of ALP (α-specific PI3K inhibitor) + FUL in pts with HR+, HER2— ABC. ALP+FUL met the primary endpoint by significantly extending progression-free survival (PFS) vs placebo (PBO) + FUL in the PIK3CA-mutant cohort (hazard ratio [HR] 0.65; 95% CI 0.50—0.85; p=0.00065; median 11.0 vs 5.7 months). Here we report overall survival (OS), subgroup data and safety in the PIK3CA-mutant cohort, and PFS by circulating tumor (ct)DNA PIK3CA mutation status in the total population. Methods: Enrollment was open to men/postmenopausal women with PIK3CA-mutant HR+, HER2— ABC and 1 prior line of endocrine therapy. Pts were randomized (1:1) to ALP (300mg/day) + FUL (500mg every 28 days and Cycle 1 Day 15) or PBO+FUL. OS was the key secondary endpoint. PFS was analyzed by PIK3CA mutant status in ctDNA, and in important prognostic subgroups, including line of treatment in ABC and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) use. Safety was analyzed in the PIK3CA-mutant cohort. Results: 341 pts in the PIK3CA-mutant cohort received ALP+FUL (n=169) or PBO+FUL (n=172). Median follow-up from randomization to data cut-off was 20.0 months. At data cut-off, 92 deaths had occurred (52% of the total 178 pts planned for final OS analysis); 40 for ALP+FUL (24%) and 52 for PBO+FUL (30%). OS results were immature at data cut-off (HR 0.73; 95% CI 0.48—1.10; p=0.06; median not estimable vs 26.9 months). There was a 45% risk reduction in PFS for pts with ctDNA PIK3CA mutations (HR 0.55; 95% CI 0.39—0.79; n=186); 20% for pts without (HR 0.80; 95% CI 0.60—1.06; n=363). PFS treatment effect for ALP+FUL vs PBO+FUL was generally consistent across subgroups of interest, with a risk reduction of 29% for pts receiving first-line (1L) treatment (HR 0.71; 95% CI 0.49—1.03; n=177), and 39% for 2L treatment (HR 0.61; 95% CI 0.42—0.89; n=161); 52% in pts with prior CDK4/6i (HR 0.48; 95% CI 0.17—1.36; n=20) and 33% in pts without (HR 0.67; 95% CI 0.51—0.87; n=321). Most frequent all-grade adverse events (AEs; ≥40% in either arm by single preferred term; ALP+FUL vs PBO+FUL) were hyperglycemia (65% vs 9%), diarrhea (54% vs 11%), nausea (46% vs 20%), and rash (40% vs 6%). Grade 3/4 AEs in ≥10% pts in either arm were hyperglycemia (fasting plasma glucose >250mg/dL; 37% for ALP+FUL vs Conclusions: ALP+FUL showed consistent clinically meaningful treatment benefit for pts with ctDNA PIK3CA mutant status, and across pt subgroups, including pts with/without prior treatment for ABC and prior CDK4/6i use. OS data were not yet mature at the data cut-off, but OS appeared numerically longer for ALP+FUL vs PBO+FUL after 52% of events. Key words: advanced breast cancer; PI3K; alpelisib; endocrine therapy Citation Format: Juric D, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu Y-S, Inoue K, Takahashi M, Pápai Z, Longin A-S, Mills D, Wilke C, Sellami D, Andre F. Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial [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 GS3-08.

Background: Patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a high risk of recurrence and death. The current standard of care is continuation of the same HER2-targeted therapy in the adjuvant setting for one year. T-DM1 has shown activity and a favorable benefit-risk profile in metastatic patients with disease progression after prior chemotherapy plus HER2-targeted therapy. Thus, T-DM1 may also be active in patients with residual invasive disease after neoadjuvant HER2-targeted therapy. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed HER2-positive (IHC3+ or ISH+) primary breast cancer (T1–4, N0–3, M0) who received neoadjuvant chemotherapy plus HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg IV q3w) or trastuzumab (6 mg/kg IV q3w), for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single versus dual neoadjuvant HER2-targeted therapy, and pathological nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint is invasive disease-free survival (IDFS). A single interim analysis (IA) was planned after approximately 67% of the IDFS events required for the primary analysis had occurred, with an efficacy stopping boundary of HR?0.732 or p Results:After review of the pre-specified IA, the IDMC recommended full analysis and disclosure of the results. With 256 IDFS events reported, administration of T-DM1 significantly improved IDFS compared with trastuzumab (unstratified HR=0.50; 95% CI: 0.39 to 0.64; p Conclusions: Adjuvant T-DM1 substantially improved IDFS in patients with HER2-positive early breast cancer with residual disease after completion of neoadjuvant therapy. Citation Format: Geyer, Jr. CE, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Fischer HH, Redondo A, Jackisch C, Jacot W, Conlin AK, Schneeweiss A, Wapnir IL, Fasching PA, DiGiovanna MP, Wuelfing P, Arce-Salinas C, Crown JP, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, von Minckwitz G. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE [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 GS1-10.

Background: Currently, patients with breast cancer (BC) with hormone receptor (HR) immunohistochemical expression between 1-9% are eligible to receive endocrine therapy. However, recent data suggest that these tumors express a basal-like molecular phenotype associated with triple negative BC (TNBC) rather than luminal phenotype associated with HR positive BC. Here, we aimed to determine the differences between strong HR positive, low HR positive and negative HR BC, in regard to responsiveness to neoadjuvant chemotherapy (NACT) and disease free survival (DFS) in large cohorts from GBG clinical trials. Methods: In this retrospective analysis of data from women with BC treated in the neoadjuvant GeparQuinto (n=2572), GeparSixto (n=588) and GeparSepto (n=1206) clinical trials, we compared patients with three HR phenotypes: low positive (ER and/or PR= 1-9%), strong positive (ER or PR= 10-100%), and negative (ER and PR= Results: Patients median age was 49 years, the majority had clinical tumor stage 2 (54.1%), negative nodal status (54.7%), and Her2 negative tumors (72.4%). 85.1% of women had BC classified as no special histological type. The pCR rate across the studies was 26.2%. 145 (3.4%) patients had low HR positive, 2417 (57.3%) strong HR positive and 1658 (39.3%) HR negative tumors. After NACT, 16.3% of patients with strong HR positive BC achieved a pCR, while among those with HR negative and low HR positive tumors, pCR rates were 40.2% and 37.9%, respectively (p Conclusions: Similarly to patients with negative HR tumors, patients with low HR positive tumors have a better responsiveness to NACT and worse survival rates, compared to patients with strongly HR positive BC. We suggest that studies on treatment options for basal-like/TNBC, should also consider including patients with low HR positive tumors. Citation Format: Villegas SL, Lederer B, Untch M, Holms F, Ulmer H-U, Diebold K, Fasching PA, Weber K, Schmitt WD, Tesch H, Rezai M, Marmé F, Sinn B, Hackmann J, Schneeweiss A, Tannapfel A, Nekljudova V, Denkert C, Loibl S. Similarities between low hormone receptor positive and hormone receptor negative breast cancer: An analysis of 4366 patients from multicenter clinical trials [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 P2-08-10.

Introduction Breast cancer diagnosed in young women who are 40 years (yrs) or younger is a relatively rare disease. However, it represents the most common cause of cancer-related deaths in this age-group. Furthermore, young age at diagnosis is associated with an increased risk of recurrence and worse survival. To date, general concepts concerning oncological cancer management should be driven by clinicopathological tumor characteristics and should adhere to standardized protocols for patients in general, but little is known about the oncological cancer treatment and outcome of this very young women in today's clinical practice. Patients and Methods The breast cancer in pregnancy registry study (BCP/GBG29/BIG 03-02) is a multicenter, international, observational study. BCP was established to investigate the oncological management and outcome of breast cancer in pregnancy. Since 2014 non-pregnant patients who are 40 yrs or younger are eligible if diagnosed with histological confirmed invasive breast cancer, independent of the type of treatment as control cohort. All patients received oncological treatment according to local standards. In this study the following endpoints will be analyzed descriptively for the young non-pregnant women cohort: breast cancer staging at diagnosis, biological characteristics of breast cancer at diagnosis, diagnostic procedures, treatment modalities, toxicity, pathological complete response after neoadjuvant chemotherapy, disease-free survival and overall survival. Results From February 2014 until June 2018, 969 non-pregnant patients ≤40 yrs have been registered. The median age at diagnosis was 35 yrs (range 19-40). Overall, 90.1% of patients had a stage T1-2 at diagnosis and 67.1% of patients had negative lymph nodes. 86.7% of tumors were invasive ductal carcinomas and 4.1% lobular carcinomas. Grading (G) 3 was reported in 55.5%. 26.6% of tumors were luminal A-like (ER- and/or PgR-positive, HER2-negative, G1-2), 40.0% luminal B-like (ER- and/or PgR-positive, HER2-negative, G3 or ER- and/or PgR-positive, HER2-positive, any G), 7.7% HER2 positive non-luminal-like, and 25.7% triple negative breast cancers. 3.8% of young non-pregnant patients had metastatic disease at primary diagnosis. Conclusion This registry comprises a large cohort of young non-pregnant patients with breast cancer diagnosed at the age of 40 yrs or younger and provides important data about a modern breast cancer treatment as well as oncological outcome in this setting of young women. Further results including oncological management, toxicity, and survival will be presented at the meeting. Citation Format: Seiler S, Schmatloch S, Reinisch M, Neunhöffer T, Schmidt M, Bechtner C, Marmé F, Wagner M, Möbus V, Reimer T, Kleine-Tebbe A, Sinn B, Stickeler E, Untch M, Janni W, Seither F, Loibl S. Cancer management and outcome of very young non-pregnant patients with breast cancer diagnosed at 40 years or younger– GBG 29 [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 P1-17-07.

Up to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital.A total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype.Patients with HER2-positive breast cancer and BMs were-when compared with HER2-negative patients-slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus60 years: hazard ratio (HR) 1.63, P0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups.We identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients.

Background In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results A significantly better DFS (hazard ratio 0.56, 95% CI 0.34–0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26–5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059). Conclusions The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

Background Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). Patients and methods This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). Results Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. Conclusions The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.