Search

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2− cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC.Significance:The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659

File with the supplementary material & methods, supplementary tables and supplementary figure.

Supplementary file with the listing of the liver genes excluded from transcriptomic analyses.

PDF file - 92K

PDF file - 53K

PDF file - 89K

PDF file - 118K

PDF file - 52K

PDF file - 82K

Supplementary Table 1 from Class III β-Tubulin Isotype Predicts Response in Advanced Breast Cancer Patients Randomly Treated Either with Single-Agent Doxorubicin or Docetaxel

PDF file - 78K

Purpose: Breast cancer in young women is associated with poor prognosis. We aimed to define the role of gene expression signatures in predicting prognosis in young women and to understand biological differences according to age.Experimental Design: Patients were assigned to molecular subtypes [estrogen receptor (ER)+/HER2−; HER2+, ER−/HER2−)] using a three-gene classifier. We evaluated whether previously published proliferation, stroma, and immune-related gene signatures added prognostic information to Adjuvant! online and tested their interaction with age in a Cox model for relapse-free survival (RFS). Furthermore, we evaluated the association between candidate age-related genes or gene sets with age in an adjusted linear regression model.Results: A total of 3,522 patients (20 data sets) were eligible. Patients aged 40 years or less had a higher proportion of ER−/HER2− tumors (P < 0.0001) and were associated with poorer RFS after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR = 1.34, 95% CI = 1.10–1.63, P = 0.004). The proliferation gene signatures showed no significant interaction with age in ER+/HER2− tumors after adjustment for Adjuvant! online. Further analyses suggested that breast cancer in the young is enriched with processes related to immature mammary epithelial cells (luminal progenitors, mammary stem, c-kit, RANKL) and growth factor signaling in two independent cohorts (n = 1,188 and 2,334).Conclusions: Proliferation-related prognostic gene signatures can aid treatment decision-making for young women. However, breast cancer arising at a young age seems to be biologically distinct beyond subtype distribution. Separate therapeutic approaches such as targeting RANKL or mammary stem cells could therefore be needed. Clin Cancer Res; 18(5); 1341–51. ©2012 AACR.

PDF file - 62K

Table S1: Summary of baseline characteristics for the current analysis cohort vs. the Remainder of HERA patients Table S2: Summary of Disease-free Survival by subgroup of patients Table S3: Summary of Overall Survival by subgroup of patients Table S4: Comparison of median follow-up time (based on reverse censoring for OS) Table S5: Predictive effect of p27 biomarker (Low/High) for DFS: Cox proportional hazards model without adjustment for other variables. Table S6: Predictive effect of p27 biomarker (Low/High) for DFS, adjusted for variables of clinical interest: Multivariate Cox proportional hazards model. Table S7: Predictive effect of p27 biomarker (Low/High) for DFS, adjusted for variables of clinical interest and the predictive effect of ER Local: Multivariate Cox proportional hazards model Table S8: Predictive effect of p27 biomarker (Low/High) for DFS, adjusted for variables of clinical interest and the predictive effect of ESR1: Multivariate Cox proportional hazards model Table S9: Predictive effect of cyclin D1 biomarker (continuous) for DFS: Multivariate Cox proportional hazards model without adjustment for other variables. Table S10: Predictive effect of cyclin D1 (continuous) biomarker for DFS, adjusted for variables of clinical interest: Multivariate Cox proportional hazards model. Table S11: Predictive effect of cyclin D1 biomarker (continuous) for DFS, adjusted for variables of clinical interest and the predictive effect of ER Local: Multivariate Cox proportional hazards model Table S12: Predictive effect of cyclin D1 biomarker (continuous) for DFS, adjusted for variables of clinical interest and the predictive effect of ESR1: Multivariate Cox proportional hazards model Figure S1. A: Histogram of TOPO2A biomarker Figure S1.B Histogram of Ki67 biomarker Figure S1.C: Histogram of Cyclin D1 biomarker Figure S1.D: Histogram of p27 biomarker Figure S2.A: Ki67 distribution by TOPO2A level Figure S2.B: Cyclin D1 distribution by TOPO2A level Figure S2.C: p27 distribution by TOPO2A level Figure S3.A: Ki67 distribution by Cyclin D1 level Figure S3.B: p27distribution by Cyclin D1 level

Quality of life; Sacituzumab govitecan; Triple-negative breast neoplasms Qualitat de vida; Sacituzumab govitecan; Neoplàsies de mama triple negatiu Calidad de vida; Sacituzumab govitecan; Neoplasias de mama triple negativo Background The antibody–drug conjugate sacituzumab govitecan (SG) prolongs progression-free survival and overall survival in patients with refractory/relapsed metastatic triple-negative breast cancer (mTNBC). Here, we investigated its effect on health-related quality of life (HRQoL). Methods This analysis was based on the open-label phase III ASCENT trial (NCT02574455). Adults with refractory/relapsed mTNBC who had received ≥2 prior systemic therapies (≥1 in the metastatic setting) were randomised 1:1 to SG or treatment of physician's choice (TPC; capecitabine, eribulin, vinorelbine, or gemcitabine). HRQoL was assessed on day 1 of each treatment cycle using the EORTC QLQ-C30. Score changes from baseline were analysed using linear mixed-effect models for repeated measures. Stratified Cox regressions evaluated time to first clinically meaningful change of HRQoL. Results The analysis population comprised 236 patients randomised to SG and 183 to TPC. For global health status (GHS)/QoL, physical functioning, fatigue, and pain, changes from baseline were superior for SG versus TPC. Compared with TPC, SG was inferior regarding changes from baseline for nausea/vomiting and diarrhoea but non-inferior for other QLQ-C30 domains. Median time to first clinically meaningful worsening was longer for SG than for TPC for physical functioning (22.1 versus 12.1 weeks, P < 0.001), role functioning (11.4 versus 7.1 weeks, P < 0.001), fatigue (7.7 versus 6.0 weeks, P < 0.05), and pain (21.6 versus 9.9 weeks, P < 0.001). Conclusions SG was generally associated with greater improvements and delayed worsening of HRQoL scores compared with TPC. This supports the favourable profile of SG as an mTNBC treatment. This work was sponsored by Gilead Sciences.

522 Background: Our preclinical findings suggest a role for the mevalonate pathway (MVA) in treatment resistance in HER2+ BC by providing alternative growth and survival signaling to bypass potent HER2 blockade, which could be overcome by the MVA inhibitors statins and nitrogen-containing bisphosphonates (NBs). Here we explored the effect of MVA inhibitors’ use on pts’ outcomes in the ALTTO trial (BIG2-06; NCT00490139). Methods: In the ALTTO trial, 8381 pts with HER2+ BC were randomized to 1 year of adjuvant lapatinib (L), trastuzumab (T), L+T, or T→L. All pts with documented treatment start with statins or NBs < 1 year after randomization were considered as MVA inhibitors users. Survival curves, with a median follow-up of 6.9 years, for disease-free survival (DFS), distant relapse-free interval (DRFI), BC-specific survival (BCSS), and overall survival (OS) according to MVA inhibitors use were estimated by the Kaplan Meier method and Log-rank test. All multivariate survival analyses employed a Cox proportional hazards regression model, adjusting for tumor size, nodal status, hormonal receptor (HoR), menopausal status, BMI, timing of chemo, and randomization arm. We considered interactions terms in Cox’s model between MVA inhibitors use and randomization arm, hormonal status, and BMI group. Results: Among the 8381 pts included in this study, 493 and 299 were statins or NBs users, respectively. Table 1 summarizes the significant differences in pts’ characteristics according to MVA inhibitors use ( P

1543 Background: Patients (pts) with cancer have increased mortality from COVID-19 and their vaccination is crucial to prevent severe infection. We aimed to identify demographic and laboratory determinants of humoral immune responses to COVID-19 vaccination in pts with cancer and investigate differences in responses based on the vaccine platform. Methods: We searched for records in PubMed, Embase, and CENTRAL up to 28/09/21, as well as conference proceedings from ASCO and ESMO 2021. We included studies of pts ≥16 yr with a cancer diagnosis, who were vaccinated against SARS-CoV-2. Studies were excluded if ≥10% of the participants had other causes of immunosuppression or baseline anti-SARS-CoV-2 spike protein antibodies (Ab)/previous COVID-19 (PROSPERO ID: CRD42021282338). For this subgroup analysis of studies that reported a proportion of pts with cancer and positive Ab titers at any timepoint following complete vaccination, a random-effects model was used to estimate the humoral response rate (HRR) with 95% confidence intervals (CI). Results: We included 64 records, reporting data from 10,511 cancer pts. The HRR in the overall population and by subgroup are shown in Table. Elder patients with hematologic cancers (59%, CI 47-70%, N = 667) and patients with lymphopenia (50%, CI 25-75%, N = 111) or hypogammaglobulinemia (36%, CI 19-57%, N=226) were the subgroups with lower HRR. Male (77%, CI 69-84%, N = 2,659) and Asian (84%, CI 54-96%, N = 37) pts showed a trend to lower HRR when compared with females and other races, respectively. Pts vaccinated with mRNA vaccine platforms (79%, CI 74-83%, N = 9,404) had numerically higher HRR than those receiving the adenovirus vaccines (28%, CI 19-40%, N = 74). Conclusions: This study highlights demographic and laboratory determinants of weaker immune responses to SARS-CoV-2 vaccination, permitting better identification of more vulnerable pts. Despite the small number of pts included receiving adenovirus vaccines, these data also suggest prioritizing mRNA platform vaccination in pts with cancer. [Table: see text]

1071 Background: Treatment goals for pts with metastatic breast cancer include extended survival and improved quality of life (QoL). SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received FDA approval for pts with mTNBC who received ≥2 prior chemotherapies (at least 1 in the metastatic setting). In the pivotal phase 3 ASCENT study (NCT02574455), SG demonstrated a significant survival benefit over single-agent chemotherapy TPC in the primary analysis population of pts with second line or greater (2L+) mTNBC without known brain metastases at baseline (Bardia A et al. NEJM 2021) and QoL (Loibl S. et al. ESMO 2021). With additional follow up, we present the final data on efficacy, including overall survival (OS), safety, and QoL. Methods: Pts with mTNBC refractory or relapsing after ≥2 prior chemotherapies with at least 1 in the metastatic setting were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) per RECIST 1.1 by independent review in pts without known brain metastases at baseline. Key secondary endpoints included OS, safety, and health-related QoL. Safety was analyzed in pts who received ≥1 dose of study drug. Results: Of 529 pts enrolled, 468 did not have known brain metastases at baseline (median age: 54 y [range, 27-82]; median prior lines: 4 [range, 2-17]). As of Feb 25, 2021 (final database lock), SG (n = 235) vs TPC (n = 233) significantly improved median PFS (5.6 vs 1.7 mo; HR: 0.39; P< 0.0001) and median OS (12.1 vs 6.7 mo; HR: 0.48; P< 0.0001). The OS rate at 24 months was 22.4% (95% CI, 16.8-28.5) in the SG arm and 5.2% (95% CI, 2.5-9.4) in the TPC arm. In the safety population (n = 482), key treatment-related grade ≥3 adverse events with SG (n = 258) vs TPC (n = 224) were diarrhea (11% vs 0.4%), neutropenia (52% vs 33%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%). There was no grade ≥3 neuropathy and 1 case of grade 3 interstitial lung disease reported with SG. No patient experienced a treatment-related death with SG, and there was 1 treatment-related death with TPC due to neutropenic sepsis. Treatment discontinuations due to AEs were ≤3% in both arms. SG arm showed clinically meaningful and statistically significant improvements than the TPC arm in scores for all five primary focus health-related QoL domains. Conclusions: The analysis based on the final database lock of ASCENT confirms the superior survival outcomes of SG over single-agent chemotherapy, with a manageable safety profile and improvement in QoL for pts with mTNBC in the 2L+ setting. These findings reinforce SG as an effective treatment option for this pt population. Clinical trial information: NCT02574455.

1537 Background: Patients (pts) with cancer are at increased risk of severe COVID-19. Both underlying malignancy and anti-cancer treatments influence the immune system, potentially impacting the level of vaccine protection achieved. Methods: A systematic literature search of PubMed, Embase, CENTRAL and conference proceedings (ASCO annual meetings and ESMO congress) up to 28/09/21, was conducted to identify studies reporting anti-SARS-CoV-2 spike protein immunoglobulin G seroconversion rates (SR) at any time point after complete COVID-19 immunization (mRNA- or adenoviral-based vaccines) in cancer pts. Complete immunization was defined as 1 dose of JNJ-78436735 vaccine or 2 doses of BNT162b2, mRNA-1273 or ChAdOx1 nCoV-19 vaccines. Subgroup analyses were performed to examine the impact of cancer diagnosis, disease stage, and anticancer therapies on the SR. Overall effects were pooled using random-effects models and reported as pooled SR with 95% confidence intervals (CI). Results: Of 1,548 identified records, 64 studies were included in this analysis reporting data from 10,511 subjects. The Table shows the SR in the overall population and specific subgroups. In pts with solid malignancies (SM), disease stage and primary site did not significantly impact the SR. In pts with hematologic malignancies (HM), SR were significantly lower in pts with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) compared to acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), and multiple myeloma (MM). Concerning the impact of cancer therapies on SR, pts with SM undergoing chemotherapy had numerically lower SR (N = 1,234, SR 87%, CI 81-92) compared to those treated with immune checkpoint inhibitors (N = 574, SR 94%, CI 88-97) or endocrine therapy (N = 326, SR 94%, CI 86-97) with or without another targeted therapy. Pts with HM treated with anti-CD20 therapy (within the last 12 months: N = 360, SR 7%, CI 2-20; or more than 12m: N = 175, SR 59%, CI 35-80), immune-modulating agents (BTK or BCL2 inhibitors) (N = 462, SR 47%, CI 32-64%) or other immunotherapies (anti-CD19/CART or anti-CD38) (N = 293, SR 37%, CI 23-53) had lower SR compared to pts treated with autologous (N = 353, SR 77%, CI 67-85) or allogenic stem cell transplantation (N = 509, SR 77%, CI 68-84). Conclusions: SR varies between cancer types and anticancer therapies with some cancer pts having low protection against COVID-19 even after complete vaccination. [Table: see text]

TPS621 Background: Human Epidermal growth factor Receptor-2 positive (HER2+) breast cancer (BC) heterogeneity can be captured at the mRNA level by the PAM50 classification. The HER2 “Enriched” (HER2-E) intrinsic subtype is encountered more often in HER2+ Hormone Receptor negative (HR-) tumors compared to HER2+ HR+ tumors and is particularly sensitive to HER2 blockade. HER2+ HR- and HER2-E achieve high pathological complete response (pCR) rates with neoadjuvant chemotherapy (CT) and dual anti-HER2 blockade with trastuzumab and pertuzumab. Additionally, the patients with pCR have improved outcomes. However, standard CT with common drugs such as anthracyclines has significant short and long-term toxicities, including cardiac events and secondary leukemias. Thus, tailoring the neoadjuvant treatment among carefully selected patients in order to reduce toxicity while preserving efficacy is a priority in early HER2-positive BC. Methods: DECRESCENDO is a large, multicentric, single-arm, phase 2 de-escalation study evaluating the efficacy of neoadjuvant CT with paclitaxel 80mg/m2 weekly or docetaxel 75mg/m2 every 3 weeks (Q3W) with pertuzumab and trastuzumab (P+T) 600/600mg fixed-dose combination (FDC) for subcutaneous (SC) injection Q3W for patients with early HER2+, HR- (ER

12084 Background: The potential gonadotoxicity of anti-HER2 agents remains largely unknown and limited conflicting evidence exists for taxanes. Anti-Mullerian hormone (AMH) is an established biomarker of ovarian reserve; its measurement during systemic therapies may aid in indicating gonadotoxicity, in the diagnosis and prediction of primary ovarian insufficiency (POI). The present analysis explored for the first time the impact of anti-HER2 therapy alone and then combined with weekly paclitaxel on ovarian reserve measured by AMH levels in breast cancer (BC) patients not previously exposed to anthracycline and cyclophosphamide. Methods: This biomarker analysis of the NeoALTTO (NCT00553358) randomized phase III neoadjuvant trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early BC with available frozen serum samples at baseline (i.e. before administering any anticancer treatment), at week 2 (i.e. “biological window” of anti-HER2 therapy alone) and/or at the time of surgery (i.e. after completion of paclitaxel plus anti-HER2 therapy and before starting adjuvant chemotherapy). Central AMH testing was performed with the Roche Elecsysâ AMH Plus assay (LoD = 0.01 ng/ml). AMH levels during anti-HER2 therapy alone and then combined with paclitaxel were assessed as a measure of treatment acute gonadotoxicity. The impact of different anti-HER2 agents, patients’ age, and baseline AMH levels on treatment gonadotoxicity were also investigated. Results: The present analysis included 130 patients with a median age of 38 years (IQR: 33-42 years). AMH values at the 3 time points differed significantly from each other (p < 0.001). At baseline, median AMH levels were 1.29 ng/mL (IQR 0.56 – 2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median value: 1.10 ng/mL, IQR 0.45 – 2.09 ng/mL, p < 0.001). At surgery, there was a larger significant decline in AMH levels (median value: 0.01 ng/mL, IQR 0.01 – 0.03 ng/mL, p < 0.001). There was no significant difference between treatment arms (trastuzumab vs. lapatinib vs. trastuzumab plus lapatinib) in the degree of reduction in AMH levels at week 2 (p = 0.763) and at surgery (p = 0.700). Age and pre-treatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk, with older age and lower AMH levels at diagnosis being associated with a greater negative impact. Conclusions: This biomarker analysis of the NeoALTTO trial showed for the first time that anti-HER2 therapies alone had limited gonadotoxicity but the addition of weekly paclitaxel resulted in marked AMH decline which likely has implications for subsequent ovarian function and fertility. These data highlight the importance of oncofertility counselling among all premenopausal women with HER2-positive BC receiving systemic anticancer treatments. Clinical trial information: NCT00553358.

Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker.In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases.A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment.Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

Purpose Overall survival (OS) can be observed only after prolonged follow-up, and any potential effect of first-line therapies on OS may be confounded by the effects of subsequent therapy. We investigated whether tumor response, disease control, progression-free survival (PFS), or time to progression (TTP) could be considered a valid surrogate for OS to assess the benefits of first-line therapies for patients with metastatic breast cancer. Patients and Methods Individual patient data were collected on 3,953 patients in 11 randomized trials that compared an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Surrogacy was assessed through the correlation between the end points as well as through the correlation between the treatment effects on the end points. Results Tumor response (survival odds ratio [OR], 6.2; 95% CI, 5.3 to 7.0) and disease control (survival OR, 5.5; 95% CI, 4.8 to 6.3) were strongly associated with OS. PFS (rank correlation coefficient, 0.688; 95% CI, 0.686 to 0.690) and TTP (rank correlation coefficient, 0.682; 95% CI, 0.680 to 0.684) were moderately associated with OS. Response log ORs were strongly correlated with PFS log hazard ratios (linear coefficient [ρ], 0.96; 95% CI, 0.73 to 1.19). Response and disease control log ORs and PFS and TTP log hazard ratios were poorly correlated with log hazard ratios for OS, but the confidence limits of ρ were too wide to be informative. Conclusion No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.

The 14th St Gallen International Breast Cancer Conference (2015) reviewed substantial new evidence on locoregional and systemic therapies for early breast cancer. Further experience has supported the adequacy of tumor margins defined as 'no ink on invasive tumor or DCIS' and the safety of omitting axillary dissection in specific cohorts. Radiotherapy trials support irradiation of regional nodes in node-positive disease. Considering subdivisions within luminal disease, the Panel was more concerned with indications for the use of specific therapies, rather than surrogate identification of intrinsic subtypes as measured by multiparameter molecular tests. For the treatment of HER2-positive disease in patients with node-negative cancers up to 1 cm, the Panel endorsed a simplified regimen comprising paclitaxel and trastuzumab without anthracycline as adjuvant therapy. For premenopausal patients with endocrine responsive disease, the Panel endorsed the role of ovarian function suppression with either tamoxifen or exemestane for patients at higher risk. The Panel noted the value of an LHRH agonist given during chemotherapy for premenopausal women with ER-negative disease in protecting against premature ovarian failure and preserving fertility. The Panel noted increasing evidence for the prognostic value of commonly used multiparameter molecular markers, some of which also carried prognostic information for late relapse. The Panel noted that the results of such tests, where available, were frequently used to assist decisions about the inclusion of cytotoxic chemotherapy in the treatment of patients with luminal disease, but noted that threshold values had not been established for this purpose for any of these tests. Multiparameter molecular assays are expensive and therefore unavailable in much of the world. The majority of new breast cancer cases and breast cancer deaths now occur in less developed regions of the world. In these areas, less expensive pathology tests may provide valuable information. The Panel recommendations on treatment are not intended to apply to all patients, but rather to establish norms appropriate for the majority. Again, economic considerations may require that less expensive and only marginally less effective therapies may be necessary in less resourced areas. Panel recommendations do not imply unanimous agreement among Panel members. Indeed, very few of the 200 questions received 100% agreement from the Panel. In the text below, wording is intended to convey the strength of Panel support for each recommendation, while details of Panel voting on each question are available in supplementary Appendix S2, available at Annals of Oncology online., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

502 Background: Pre-specified 5-year analyses of the phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial defined in Amendments 11&12. Methods: From June 2007 to July 2011, 8381 patients (pts) were randomised from 946 sites in 44 countries to receive either L+T, T→L, L, or T. In 2011, due to futility the L arm was closed and is not included in this analysis. The primary end point is disease-free survival (DFS). Secondary objectives include treatment comparisons with respect to overall survival (OS), time to recurrence (TTR), time to distant recurrence (TDR), cardiac and overall safety and tolerability. Primary analysis results of the study were published in JCO 2015 34:1034-1042. This updated analysis occurs at a 6.9 yrs median follow up (MFU). Results: All patients have reached 5-years of follow-up. 705 DFS events for L+T vs T have been observed. HR for DFS was 0.86 (95% CI, 0.74-1.00; 6-yr DFS%=85% vs 82%) for L+T vs T and 0.93 (95% CI, 0.81-1.08; 6-yr DFS%=84% vs 82%) for T→L vs. T. The 6-year OS was 93%, 92%, and 91% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T vs. T and 0.88 (95% CI, 0.71-1.08) for T→L vs. T. DFS differences for L+T vs. T were slightly higher for the hormone-receptor(ER)-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS%=84% vs. 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS%=83% vs.79%)] subgroups. There were no differences in sites of first DFS events according to treatment arm for CNS, loco-regional, or distant recurrences. There were more AEs related to study treatment (L+T 93% vs T 64%). The incidence of primary cardiac end points was low: 1% for L+T, 0.5% for T→L and 0.9% for T. Conclusions: The HRs for this updated analysis are similar to those from the Primary Analysis and the event rate remains lower than anticipated (705 vs 850 planned). Cardiac toxicity remains low. This analysis suggests that HER2+/ER- tumors may have a different biology than HER2+/ER+ and may benefit more from dual HER2 blockade. Long-term follow up continues. Clinical trial information: NCT00490139.

TPS613Background: Taselisib is an orally bioavailable, potent, selective inhibitor of Class I PI3-kinase (PI3K) alpha, gamma, and delta isoforms, with 30-fold less inhibition of the PI3K beta isofo...

The human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in up to 25% of breast cancer patients, and this feature is associated with an aggressive phenotype, a high recurrence rate, and reduced survival. Until recently, combination chemotherapy was the most effective and only adjuvant treatment for HER2-positive patients. Trastuzumab, a monoclonal antibody directed against the HER2 extracellular domain, has recently demonstrated highly reproducible and astonishing benefit in halving the recurrence rate and reducing mortality in five adjuvant breast cancer trials. But such unfettered success has come at a cost, both in terms of cardiotoxic risk and substantial financial burden. Though trastuzumab has been able to significantly improve clinical outcomes of many patients with early breast cancer, the reality is that an unacceptable proportion will still relapse. Beyond trastuzumab, what is the next step for these HER2-positive breast cancers? This review first discusses the individual results of the five adjuvant trastuzumab studies in terms of efficacy and safety, highlighting their similarities and differences. It also evaluates the current status of trastuzumab as a result of these studies and explores the possible future direction for HER2-positive breast cancers in light of recent advances in translational oncology.

To date, most treatment decisions for adjuvant chemotherapy in breast cancer are sed on conventional clinicopathological criteria. Since breast cancer tumors with similar clinicopathological characteristics can have strikingly different outcomes, the current selection for adjuvant chemotherapy is far from accurate. Using high-throughput microarray analysis, a 70-gene signature was identified which can accurately select early stage breast cancer patients who are highly likely to develop distant metastases, and therefore, may benefit the most from adjuvant chemotherapy. This review describes the development of the 70-gene profile (Mammaprint), its retrospective validation and feasibility studies, and its prospective validation in the large adjuvant MINDACT (Microarray In Node-negative Disease may Avoid ChemoTherapy) clinical trial.

background Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. methods This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. results Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P

This combined, retrospective analysis compared once-per-chemotherapy-cycle pegfilgrastim with daily Filgrastim in breast cancer patients undergoing myelosuppressive chemotherapy enrolled in two similarly designed, randomized, double-blind, pivotal trials. On day 2 of each chemotherapy cycle, a single subcutaneous (SC) injection of pegfilgrastim [either 6 mg (n=77) or 100 microg/kg (n=149)] was administered, or daily Filgrastim SC injections (5 microg/kg/day; n=222) were initiated and continued until either absolute neutrophil count (ANC)or =10 x 10(9)/l after the expected nadir or for up to 14 days, whichever occurred first. Individually, each of these trials demonstrated that a single pegfilgrastim injection per cycle is as effective at reducing the duration of severe neutropenia as daily injections of Filgrastim. Clinical efficacy data from the two trials were combined for analysis (n=448). The risk of febrile neutropenia (FN; absolute neutrophil count0.5 x 10(9)/l with feveror =38.2 degrees C) was significantly lower [11% vs 19%, respectively; relative risk = 0.56 (95% confidence interval: 0.35, 0.89)] in patients receiving pegfilgrastim than for those receiving Filgrastim. Trends towards lower risks of hospitalization and intravenous anti-infective use were also observed. These observations were consistent irrespective of risk factors, including age, disease stage, performance status and prior treatment. Pegfilgrastim may offer patients more effective protection against neutropenic complications of chemotherapy with fewer injections and less disruption to their lives.

Docetaxel has proven efficacy in metastatic breast cancer. In this pilot study, we explored the efficacy/feasibility of docetaxel-based sequential and combination regimens as adjuvant therapy of node-positive breast cancer.From March 1996 till March 1998, four consecutive groups of patients with stages II and III breast cancer, agedor = 70 years, received one of the following regimens: a) sequential Doxorubicin (A) --Docetaxel (T) --CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil): A 75 mg/m q 3 wks x 3, followed by T100 mg/m2 q 3 wks x 3, followed by i.v. CMF Days 1+8 q 4 wks x 3; b) sequential accelerated A --T --CMF: A and T administered at the same doses q 2 wks with Lenograstin support; c) combination therapy: A 50 mg/m2 + T 75 mg/m2 q 3 wks x 4, followed by CMF x 4; d) sequential T --A --CMF: T and A, administered as in group a), with the reverse sequence. When indicated, radiotherapy was administered during or after CMF, and Tamoxifen after CMF.Ninety-three patients were treated. The median age was 48 years (29-66) and the median number of positive axillary nodes was 6 (1-25). Tumors were operable in 94% and locally advanced in 6% of cases. Pathological tumor size was2 cm in 72% of cases. There were 21 relapses, (18 systemic, 3 locoregional) and 11 patients (12%) have died from disease progression. At median follow-up of 39 months (6-57), overall survival (OS) was 87% (95% CI, 79-94%) and disease-free survival (DFS) was 76% (95% CI, 67%-85%).The efficacy of these docetaxel-based regimens, in terms of OS and DFS, appears to be at least as good as standard anthracycline-based adjuvant chemotherapy (CT), in similar high-risk patient populations.

HER-2/neu status was determined by immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) methods in more than 300 paraffin-embedded primary breast cancer samples.HER-2/neu status was determined by FISH using the PathVysion kit (Vysis) and by IHC using either a monoclonal antibody CB11 or a cocktail of antibodies: the monoclonal TAB250 and the polyclonal pAb1.Of the 324 cases evaluable by IHC, 65 out of 318 (20%) and 24 out of 324 (7%) were scored as positive when using the antibody cocktail and the CB11, respectively. HER-2/neu gene amplification occured in 64 out of 324 cases (20%). Concordance of FISH and IHC was found in 285 out of 318 cases (90%) and 278 out of 324 cases (86%) using the cocktail and the CB11, respectively.The cost-effectiveness analysis revealed that the use of a sensitive IHC method followed by confirmation of positive results by FISH considerably decreased the FISH costs and may become standard practice for HER-2/neu evaluation.

The purpose of this study is to evaluate HER-2 and topoisomerase IIalpha (topo IIalpha) as candidates for predicting the activity of anthracyclines in the adjuvant treatment of breast cancer patients.In this study, we evaluated HER-2 and topo IIalpha gene aberrations by fluorescence in situ hybridization in a series of 430 primary breast cancer samples. Samples came from node-positive breast cancer patients randomly treated either with one of two anthracycline-based regimens [full-dose epirubicin-cyclophosphamide (HEC) and moderate-dose epirubicin-cyclophosphamide (EC)] or with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in the context of a Phase III adjuvant therapy trial. Event-free survival comparisons were performed between the three study arms in the subgroups of HER-2-amplified and nonamplified tumors. An explorative analysis was also performed to evaluate the predictive value of topo IIalpha in the cohort of HER-2-amplified patients.HER-2 amplification was observed in 73 of the 354 evaluable samples (21%), whereas topo IIalpha amplification was found in 23 of the 61 evaluable HER-2-amplified tumors (38%). The three event-free survival comparisons were CMF versus HEC, CMF versus EC, and EC versus HEC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were as follows: (a) CMF versus HEC, HR = 1.42 for HER-2-amplified tumors (95% CI, 0.54-3.76; P = 0.48) and 0.84 for HER-2-nonamplified tumors (95% CI, 0.49-1.44; P = 0.53); (b) CMF versus EC, HR = 1.65 for HER-2-amplified tumors (95% CI, 0.66-4.13; P = 0.29) and 0.66 for HER-2-nonamplified tumors (95% CI, 0.39-1.10; P = 0.11); and (c) EC versus HEC, HR = 0.93 for HER-2-amplified tumors (95% CI, 0.31-2.77, P = 0.90) and 1.33 for HER-2-nonamplified tumors (95% CI, 0.82-2.14; P = 0.25). Observed HRs suggest that the anthracycline-based therapy could be more effective than CMF in the subgroup of HER-2-amplified patients, whereas treatments could be equally active in the HER-2-nonamplified cohort. topo IIalpha evaluation suggests that the superiority of anthracyclines over CMF in HER-2-amplified patients could be confined to the subgroup of topo IIalpha-amplified tumors.HER-2 could have a predictive value for the activity of anthracycline-based regimens in the adjuvant therapy of breast cancer patients. The predictive value of HER-2 would most likely be related to the concomitant amplification of the topo IIalpha gene.

142 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 in EVE + EXE arm and 70 in EXE arm) whose baseline characteristics and clinical outcome were comparable to the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE + EXE over EXE was maintained in the subgroups defined by each of the 9 genes with a mutation rate >10% (e.g., PIK3CA, FGFR1, CCND1) or when less frequently mutated genes (e.g., PTEN, AKT1) were included in their respective pathways. Patients with 0 or 1 genetic alteration in PI3K or FGFR pathways or CCND1 had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. The preliminary results suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2– BC will be further investigated. Clinical trial information: NCT00863655.

LBA509 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone-receptor positive (HR+), HER2-negative (HER2-) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using both univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 and 70 in EVE+EXE and EXE arms, respectively) whose baseline characteristics and clinical outcome were comparable with the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE+EXE over EXE is maintained in the subgroups defined by each of the nine genes with a mutation rate >10% (eg, PIK3CA, FGFR1, and CCND1), or when less frequently mutated genes (eg, PTEN, AKT1) were included in their respective pathways. Patients with no or only 1 genetic alteration in PI3K or FGFR pathways, or CCND1, had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity/resistance to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. It demonstrated the feasibility of applying large-scale NGS and subsequent correlative analysis to such trials. The observations suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways, or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2- BC will be further investigated. Clinical trial information: NCT00863655.

During the past year, the literature on adjuvant systemic therapy for breast cancer has focused on three main areas of interest. First, new information on biologic factors that might help in the determination of prognosis has been released but is still unlikely to have an impact on daily clinical practice. More important in this regard is the issuing by a consensus panel of practical recommendations for the treatment of node-negative breast cancer according to classic and well-validated prognostic and predictive factors. Second, new therapeutic strategies such as increasing the dose intensity of chemotherapy or incorporating new drugs into adjuvant regimens have been further explored. In addition, important new data regarding the optimal duration of tamoxifen administration in the adjuvant setting have been provided by a Swedish and a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial. Lastly, increased attention has been given to the toxicity of systemic adjuvant therapy, and new considerations such as preservation of quality of life have been taken into account.