Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.

Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

507 Background: Hormonal therapy (HT) is the mainstay for patients (pts) with ER+ BC. P, a cyclin-dependent kinase 4/6 inhibitor, blocks growth of ER+/HER2– BC preclinical models. In PALOMA-1, an open-label Ph 2 trial, addition of P to L improved median PFS vs L alone (20.2 months [mo] vs 10.2 mo) in pts with first-line ER+/HER2– ABC with acceptable safety, leading to accelerated FDA approval. PALOMA-2 is a randomized double-blind Ph 3 trial designed to confirm these results. Methods: 666 postmenopausal pts with no prior systemic therapy for ABC were randomized 2:1 to receive P (oral 125 mg/d; 3 wks on/1 wk off) + L (2.5 mg/d continuously) or PLB + L every 28 days until disease progression, consent withdrawal or death. Pts were stratified by disease site, disease-free interval from end of (neo)adjuvant therapy, and prior HT (yes/no). Primary endpoint: investigator-assessed PFS; key secondary endpoints: overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR=CR + PR + SD ≥24 wks), patient-reported outcomes and safety. Tumor assessments were every 12 wks. 347 events were needed with 90% power to detect a hazard ratio (HR) ≤0.69 in favor of P+L (1-sided α=0.025). Results: By 26 Feb 2016, 331 PFS events occurred. Baseline characteristics were well balanced. Median PFS was 24.8 mo (P+L) vs 14.5 mo (PLB+L) (HR=0.58 [0.46–0.72], P<0.000001). ORR was improved with P+L (42.1% vs 34.7%, P=0.031; 55.3% vs 44.4% in pts with measurable disease [P=0.013]). CBR was 84.9% vs 70.3% (P<.0001). Common adverse events (AEs; all grades) with P+L vs PLB+L were neutropenia (79.5% vs 6.3%), fatigue (37.4% vs 27.5%), nausea (35.1% vs 26.1%), arthralgia (33.3% vs 33.8%) and alopecia (32.9% vs 15.8%). Most common severity seen was G3 for neutropenia (56.1%) and G1 for the other AEs. Febrile neutropenia was seen only with P+L (2.5%). Permanent discontinuation due to AEs was 9.7% (P+L) vs 5.9% (PLB+L). OS data are immature; final OS analysis is pending. Conclusion: PALOMA-2 expands and confirms the significant clinical benefit and safety of P+L in ER+/HER2– ABC pts who had not received prior systemic therapy for their advanced disease. Clinical trial information: NCT01740427.

Aim: The Make Your Dialogue Count survey aimed to explore communication gaps between patients/caregivers and oncologists, and the needs of patients/caregivers at diagnosis and most recent treatment change. Methods: Three distinct sets of parallel questions were asked of 359 women with metastatic breast cancer, 234 caregivers and 252 oncologists. Survey respondents were not necessarily associated with each other. Results: Patients/caregivers considered themselves knowledgeable, yet many lacked basic disease information affecting treatment decisions. Patients/caregivers reported that oncologists do not discuss important topics at diagnosis. Patients failed to discuss side effects, but wanted their oncologist's help to manage side effects. Conclusion: This survey provides additional insight on interactional dynamics to bridge gaps in understanding that affect quality of care.

1000 Background: The ABC adjuvant trials (5/2007-11/2013) were developed by USOR and NSABP to determine if a regimen of TC for 6 cycles is non-inferior to combination regimens of doxorubicin/cyclophosphamide with docetaxel or paclitaxel (TaxAC) in women with resected high-risk, HER2-negative breast cancer. 1870 patients (pts) from B-49 were combined with 1077 from the TaxAC and TC groups of B-46-I/USOR 07132, and 1295 from USOR 06-090, for a total of 4242. A detailed history of this collaborative effort will be discussed. Methods: The primary endpoint was invasive disease-free survival (iDFS), defined as time to local, regional or distant recurrence, invasive contralateral breast cancer, second primary cancer, or death. Pts were stratified for: parent trial, pos nodes (0, 1-3, 4-9, 10+), and hormonal status (neg, pos). A hazard ratio (HR) from a stratified Cox model of 1.18 or more was pre-defined as inferior. HRs above 1 favor TaxAC. Our pre-specified interim monitoring plan was to report early for futility if HR was >1.18 when 334 iDFS events were observed (50% of planned 668 events for definitive analysis). Results: 2078 pts randomized to TC and 2052 to TaxAC (total 4130) began assigned therapy and comprise the analysis set. Median follow-up: 3.2 yrs. Pt and tumor characteristics are balanced by treatment: 69% hormone pos, 41% node neg, 51% high grade. With 334 iDFS events, observed HR for TC v TaxAC is 1.202 (95% CI 0.97-1.49), which exceeds 1.18, thus we are reporting early for futility. With 397 iDFS events, 3 yr iDFS is 91.7% for TC v 92.4% for TaxAC. For TNBC: 86.6% v 89.6%, HR, 1.42, (1.04-1.94). For hormone pos: 94.1% v 93.7%, HR, 1.08 (0.84-1.40). Tests for treatment interaction by hormone receptor, nodal status, and protocol were negative. Conclusions: Statistical non-inferiority of the non-anthracycline regime could not be demonstrated. Longer follow-up should clarify the clinical utility of these initial findings. SUPPORT: U10CA-180868, -21115, -189867, -180822, -180820; 180821; 180791; Genentech Clinical trial information: NCT01547741.

Abstract Approximately 232,670 cases of breast cancer will be diagnosed in the US in 2014, of which 86,088 (37%) cases will involve cancer that has spread regionally or metastasized. The 2013 Global Count Us, Know Us, Join Us survey found that 53% of women with advanced breast cancer (ABC; breast cancer that has spread to distant parts of the body) surveyed in the US wish they had more time to discuss their needs during clinic visits, and 60% believe their cancer treatment options are limited. To better understand unmet patient needs and potential communication gaps in treatment discussions with physicians, surveys were developed for women with ABC, their caregivers, and oncologists. The Make Your Dialogue Count survey will be conducted online, by paper, and by telephone in the US from June through August 2014. Survey respondents must be (1) women ≥21 years of age diagnosed with ABC; (2) their caregivers who attend at least half the clinic visits; or (3) licensed US medical oncologists who treat ≥5 women with ABC per month. Patient and caregiver data were not weighted. Oncologist data regarding geographic region and years in practice by gender were weighted to align with actual proportions in the population. Final results of the full survey are expected by September 30, 2014. The Make Your Dialogue Count survey will explore issues such as the emotional impact of diagnosis of ABC; the doctor-patient relationship, including the quality of communications and information exchange during clinic visits; and the effect of side effects on treatment choice and satisfaction, from the perspectives of patients, their caregivers, and oncologists. Findings from the Make Your Dialogue Count survey will provide insight into the doctor-patient relationship from multiple perspectives. Comparing responses given by patients, caregivers, and oncologists can identify potential communication gaps that could be affecting the quality of care provided. Considering the number of women living with ABC, our findings could help oncologists to meet the emotional and informational needs of their patients, and provide patients with the supportive treatment environment they seek and the most relevant disease and treatment information possible. Citation Format: Musa Mayer, Helen L Coons, Stephen Jones, Deana Percassi. Understanding potential gaps in treatment discussions between caregivers/patients with advanced breast cancer and oncologists [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-10-08.

Abstract Background Early stage HER2 amplified breast cancer has a generally favorable prognosis with over 95% of patients showing 2-year disease free survival (DFS) when treated with adjuvant trastuzumab. However, a subset of these tumors are refractory to treatment and present a challenge for the oncologist, particularly when clinical and histologic parameters, including the patient’s nodal and hormonal status, are indicative of lower-risk HER2 positive disease. In this study we describe the genomic landscape of three clinically lower-risk patients with HER2 amplified tumors who relapsed on adjuvant docetaxel and cyclophosphamide plus 1 year of trastuzumab in a phase 2 study (Jones et al, Lancet Oncology 14: 1121, 2013). All patients’ tumors showed high-level HER2 amplification ratios by FISH (8.51-14.46) and were analyzed in parallel with a fourth clinically matched 2-year DFS patient’s tumor from the same trial with high HER2 gene amplification (FISH ratio 11.38). Methods Primary tumor genomic DNA analysis was performed from archival tissue by next generation sequencing (NGS) on the Illumina HiSeq 2500 platform in a CLIA certified laboratory. Tumors were screened for point mutations and copy number alterations (CNAs) by NGS using a targeted-whole exome 613 gene panel. CNAs detected by NGS were confirmed on a DNA microarray featuring high-density probe coverage of the same 613 genes on the targeted panel. CGH chromosome ratio plots were overlaid with algorithmically derived NGS copy number data to generate a map of the chromosomal genomic landscape for each patient’s tumor. Results High-level HER2 gene amplification status was confirmed, and co-amplified chromosome 17 genomic regions were detected in all three relapsed patients’ tumors. High-level HER2 amplification was also confirmed in the non-relapsed patient’s tumor but co-amplified regions were not detected on chromosome 17 or elsewhere in this patient’s tumor genome. Two of the relapsed ER negative tumors shared focal high-level CCNE1 gene amplifications on chromosome 19. High-level MAP3K3 gene amplification on chromosome 17 was detected in the one ER positive tumor from a relapsed patient. Focal PIK3CA gene amplifications were not identified in any of these tumors, but two tumors (one from the relapse group and one non-relapse) were positive for activating H1047R mutations. Conclusions Combined NGS and CGH analysis of HER2 positive early stage breast cancer can be performed in the clinical laboratory to reveal the tumor’s chromosomal genomic landscape. Combined with other test results, this tumor map can help identify patients at high-risk for relapse and reveal alternative predictive biomarkers of therapeutic response. Citation Format: Shelly Gunn, Chris McCaskill, Linda Daley, Agnes Puskas, Lina Asmar, Yunfei Wang, Stephen Jones. The chromosomal genomic landscape and targetable co-amplified genes in HER2 positive breast cancer patients who relapsed on an adjuvant trastuzumab chemotherapy trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-18.

e20575 Background: About 5% of newly diagnosed BC cases in the US are metastatic, and up to 30% of women diagnosed with early-stage BC later develop MBC. The Make Your Dialogue Count survey probed potential gaps in doctor-patient discourse. Methods: The survey was conducted (June-August 2014) online, by paper, and by telephone among US women (age ≥ 21 y) with MBC and licensed US medical oncologists who treat ≥ 5 women with MBC per month. Survey respondents were not necessarily associated with one another. Patient data were unweighted. Oncologist data were weighted by geographic region and years in practice by sex to match proportions in the population. Statistically significant differences between groups were determined by standard t-test of column proportions and means at the 95% confidence level. Results: The survey was completed by 359 women (median age 53 y) and 252 oncologists (median 15 y in practice). At initial MBC diagnosis, oncologists practicing longer ( ≥ 15 vs < 15 y) were more likely to feel it is important/very important to discuss side-effect management (95%* vs 84%); yet only 58% of patients stated that this topic was actually discussed. At the time of treatment change, oncologists practicing longer were more likely to perceive in their patients anxiety about managing treatment side effects (80%* vs 60%) and adjusting to a new regimen (78%* vs 61%), and determination to treat their MBC without interfering with daily life (56%* vs 36%); only 44%, 33%, and 41% of patients reported having these feelings, respectively. Oncologists practicing longer were more likely to strongly agree that they wish they could do more to help patients manage side effects (53%* vs 34%). Oncologists practicing longer were less likely to let their emotions keep them from providing some information to patients (17%* vs 29%). Notwithstanding, oncologists practicing longer (31%) and shorter (24%) sometimes did not discuss with patients that MBC is incurable. *Significance at 5% risk level. Conclusions: Our findings suggest that oncologist-patient dialogue must improve to ensure that doctors understand and address patient needs and that frank discussions of difficult and/or emotional topics occur.

AbstractPurpose: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T).Experimental Design: Treatment comprised eight cycles of AC→T (T dose: 100 mg/m2 on day 1) or AC→XT (X dose: 825 mg/m2 twice daily, days 1–14; T dose: 75 mg/m2 on day 1). The primary endpoint was 5-year disease-free survival (DFS).Results: Of 2,611 women, 1,304 were randomly assigned to receive AC→T and 1,307 to receive AC→XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67–1.05; P = 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC→XT versus AC→T (HR, 0.68; 95% CI, 0.51–0.92; P = 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)–positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of <10% or <20%, respectively, and only 17 (2%) and 53 (6%) DFS events, respectively, occurred in these groups at 7 years.Conclusions: The very low event rate in patients with ER-positive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients. Clin Cancer Res; 21(19); 4305–11. ©2015 AACR.

1015 Background: This study was to assess health resource utilization in patients with breast cancer (BC) treated with generic (available in US since 2011) vs branded docetaxel. Methods: A retrospective inception cohort was analyzed in Clinformatics DataMart healthcare claims database. Patients (female, aged ≥18 years) were identified between Apr 1, 2011 and Jun 30, 2012 if they had an ICD-9:174 for BC, initiated docetaxel, and had 6-month continuous insurance coverage pre (baseline) and post (follow-up) docetaxel initiation. The 50 most frequent claims for clinical diagnoses, procedures and prescriptions were evaluated between generic and branded docetaxel along with health resource utilization and expenditures, with hierarchical mixed effects model adjustment for potential confounding. Results: 1,955 patients diagnosed with BC were identified, of which a total of 98 generic and 262 branded docetaxel users were included in the final analysis. For the majority of patients, the source of docetaxel was not apparent. Patient characteristics were comparable at baseline between study groups. During follow-up, the generic cohort showed a higher rate of claims for neutropenia (67.3% vs 48.9%; p<0.01) and malaise and fatigue (22.4% vs 13.7%; p<0.05) among medical diagnoses. The branded was higher in nausea and vomiting (43.5% vs 29.6%; p=0.02). The rate of neutropenia remained higher in generic vs branded (73.9% vs 52.8%; p<0.01) even after adjusting for history of neutropenia and baseline use of G-CSF and fosaprepitant. The generic cohort had more fosaprepitant use at follow up (54.1% vs 30.2%; p<0.01). The higher odds of neutropenia was observed in generic with (OR=2.49; p= 0.03) or without (OR=1.41; p= 0.31) fosaprepitant use during follow up. Mean outpatient costs excluding docetaxel drug costs were higher in the generic ($59,177 vs $50,243; p<0.01), and remained significantly higher ($54,282 vs $46,698; p=0.03) after adjustment for baseline healthcare costs, inpatient admissions, etc. Conclusions: Use of generic vs branded docetaxel in BC was associated with about 40% more medical claims for neutropenia and higher ambulatory care costs at 6 months follow up. Further research is needed to confirm these findings.

Purpose Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Patients and Methods Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. Results A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. Conclusion Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.

Abstract Background: USON 01062 (O’Shaughnessy J, et al. Proc SABCS, 2010, abst S4-2) showed no improvement in the primary endpoint of disease-free survival (DFS) (median FU 5 yrs: HR 0.84, 95% CI: 0.67-1.05; p = 0.125) with the addition of capecitabine (X) to standard adjuvant chemotherapy, but showed improvement in OS (HR 0.68, 95% CI: 0.51-0.92; p = 0.011). Exploratory analysis of local pathology-assessed Ki67 suggested benefit from adjuvant X in pts with more highly proliferative cancers with Ki67 ≥ 10% (Pippen J et al. Proc ASCO, 2011, abst 500). The objective of this study is to determine whether centrally-performed Ki67 IHC results corroborate or refute this finding. Methods: 2610 pts with resected high risk EBC were randomized to receive 4 cycles of AC (doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2) IV every 3 wks for 4 cycles followed by either docetaxel 100mg/m2 IV or docetaxel 75mg/m2 IV plus X 825mg/m2 PO bid for 14 days every 3 wks for 4 cycles. Archival primary breast cancer tissue was collected on 2000 pts for predictive biomarker analyses. Central Ki67 IHC was performed using the anti-Ki67 monoclonal antibody SP6 and was read by one pathologist (HK) according to published recommendations (Dowsett M, et al. JNCI 103:1-9, 2011). Results: Central Ki67 IHC has been performed on 1440 pts who had centrally-validated informed consents. The distribution of% Ki67-positive cells by locally-assessed ER/HER2 subtype is shown below. 45% of HR+ HER2- BCs had a Ki67 ≤ 10%, while 24% had a Ki67 11% to 20%, and 31% had a Ki67 > 20%. The concordance between the local vs central Ki67 results was low at 46% for Ki67 <10%, 49% for Ki67 10%-20%, and 76% for Ki67 > 20%. The central Ki67 results tended to be higher than the local testing results. Central mRNA classifiers were developed for ER, PR, HER2 and Ki67 using Fluidigm Microfluidics Dynamic Arrays and correlate highly with central IHC assessment of these markers. Conclusions: HR+ HER2- EBC is enriched for cancers with a low proliferative rate, a group of pts unlikely to benefit from the cell cycle-specific cytotoxic agent, capecitabine. Analyses of the impact of adjuvant X added to AC/T in EBC pts according to ER status, and according to Ki67 (analyzed as a binary and continuous variable) will be performed prior to SABCS, 2013. Number of Patients% Ki67 Pos CellsTotal *HR+TNHER2+/HR+HER2+/ HR-0-104163622222711-151391066151016-20126871615821-3018411539201031-1005751403423555Total144081042510790*Totals do not equal sum of subtype categories due to missing HER2 information Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-01.

Background Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplifi ed early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplifi ed and TOP2A-non-amplifi ed disease.Methods This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplifi ed early stage breast cancer; operable, histologically confi rmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m y, plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplifi ed and TOP2A-non-amplifi ed patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials. gov, number NCT00493649.Findings 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36 . 1 months (IQR 35 . 5-36 . 7), 2-year DFS was 97 . 8% (95% CI 94 . 2-99 . 2) and 2-year overall survival was 99 . 5% (95% CI 96 . 2-99 . 9) for the 190 patients with TOP2A-amplifi ed disease; 2-year DFS was 97 . 9% (95% CI 94 . 9-99 . 1) and 2-year overall survival was 98 . 8% (95% CI 96 . 2-99 . 6) for the 248 patients with TOP2A-non-amplifi ed disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58 . 4%), neutropenia (250, 51 . 4%), and nausea (217, 44 . 7%). The most common grade 3-4 toxic eff ects were neutropenia (229, 47 . 1%), febrile neutropenia (30, 6 . 2%), fatigue (21, 4 . 3%), and diarrhoea (16, 3 . 3%). Cardiac dysfunction occurred in 29 (6 . 0%) patients (12 [2 . 5%] grade 1, 15 [3 . 1%] grade 2, and two [0 . 4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction.Interpretation A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplifi ed early breast cancer, irrespective of TOP2A status.

TPS652 Background: Palbociclib (PD-0332991) is an orally bioavailable selective inhibitor of CDK4/6 that prevents DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. In a randomized phase II trial comparing palbociclib (PD-0332991) plus letrozole (P + L) to letrozole (L) in postmenopausal women with ER(+), HER2(–) advanced breast cancer (ABC) who had not received any prior systemic anticancer therapy for their advanced disease, P + L demonstrated significantly longer progression-free survival (PFS) vs L (26.1 vs 7.5 mo; HR = 0.37, P < .001) and was generally well tolerated, with uncomplicated neutropenia as the most frequent adverse event (Finn et al SABCS 2012). Methods: Based on phase II data, a global, randomized, double-blind, phase III clinical trial was designed to demonstrate that P + L provides superior clinical benefit compared with L + placebo in postmenopausal women with ER(+), HER2(–) ABC who have not received any prior systemic therapy for their advanced disease. The study aims to assess whether P + L improves median PFS over L at HR of at least 0.7. Approximately 450 eligible patients with locoregionally recurrent or metastatic, pathologically confirmed ABC who are candidates to receive L as first-line treatment for their advanced disease will be randomized 2:1 to receive either P (125 mg QD 3 wk on, 1 wk off) + L (2.5 mg QD) or L (2.5 mg QD) + placebo. Patients who received anastrozole or letrozole as part of their (neo)adjuvant regimen are eligible if their disease progressed more than 12 months from completion of adjuvant therapy. Tumor tissue is required for participation. Secondary endpoints include overall survival, objective response, duration of response, clinical benefit, safety and tolerability, and patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms. Clinical trial information: NCT01740427.

Background and purpose The TEAM trial investigated the efficacy and safety of adjuvant endocrine therapy consisting of either exemestane or the sequence of tamoxifen followed by exemestane in postmenopausal hormone-sensitive breast cancer. The present analyses explored the association between locoregional therapy and recurrence (LRR) in this population. Material and methods Between 2001 and 2006, 9779 patients were randomized. Local treatment was breast conserving surgery plus radiotherapy (BCS + RT), mastectomy without radiotherapy (MST-only), or mastectomy plus radiotherapy (MST + RT). Patients with unknown data on surgery, radiotherapy, tumor or nodal stage (n = 199), and patients treated by lumpectomy without radiotherapy (n = 349) were excluded. Results After a median follow-up of 5.2 years, 270 LRRs occurred (2.9%) among 9231 patients. The 5-years actuarial incidence of LRR was 4.2% (95% CI 3.3–4.9%) for MST-only, 3.4% (95% CI 2.4–4.2%) for MST + RT and 1.9% (95% CI 1.5–2.3%) for BCS + RT. After adjustment for prognostic factors, the hazard ratio (HR, reference BCS + RT) for LRR remained significantly higher for MST-only (HR 1.53; 95% CI 1.10–2.11), not for MST + RT (HR 0.78; 95% CI 0.50–1.22). Conclusion This explorative analysis showed a higher LRR risk after MST-only than after BCS + RT, even after adjustment for prognostic factors. As this effect was not seen for MST + RT versus BCS + RT, it might be explained by the beneficial effects of radiation treatment.

590 Background: Some ER-negative (ER-) breast cancers express low levels of estrogen receptors and approximately 12% express androgen receptors (Traina, T, et al. ASCO, 2012). Whether young premenopausal women (age <40) with ER- breast cancer (BC) who are more likely to retain ovarian function after adjuvant chemotherapy have a worse outcome than older women with ER- disease has not been widely investigated. Methods: We analyzed 2 adjuvant US Oncology BC studies: 99-016, 1830 BC patients randomized to doxorubicin/cyclophosphamide (AC)→Paclitaxel (P) (AC/P) vs AP→weekly P (no cyclophosphamide [C]) (AP/wP); and 01-062, 2611 patients randomized to AC→docetaxel (T) vs AC→T plus capecitabine (XT). ER+ patients received standard endocrine therapy following chemotherapy. Five-year DFS results did not show significant differences between the treatment arms on either study. The outcomes were analyzed for 5-year DFS by age ≤40yrs and >40yrs and by ER status. Results: In the two studies combined, ER- patients ≤40 had a superior DFS (84%) than ER- patients >40 (80%), while ER+ patients ≤40 had a worse 5-yr DFS (83%) than ER+ patients >40 (89%), although these findings were of borderline significance (see Table below). In 99-016, omitting C did not adversely affect outcomes in either age group, regardless of ER status. Conclusions: We did not observe worse outcomes in ER- patients ≤40 years compared to those >40 years in 2 US Oncology adjuvant chemotherapy trials, suggesting no adverse impact of assumed greater ovarian function following adjuvant chemotherapy in patients ≤40yrs. ER+ patients ≤40 had a worse DFS than ER+ patients >40. Omitting C in ER- patients ≤40 or >40 did not adversely affect outcome. [Table: see text]

PURPOSE:Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane. Now, with longer follow-up, a large number of non-breast cancer-related events have been reported. Exploratory analyses describe breast cancer-free survival (BCFS) and explore incidence and patterns of the different competing events.PATIENTS AND METHODS:Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) -positive and 547 with ER-unknown tumors.RESULTS:In all, 930 BCFS events have been reported (exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of 0.81 (95% CI, 0.71 to 0.92; P = .001) in favor of exemestane in the ER-positive/ER unknown group. Analysis partitioned at 2.5 years after random assignment showed that the on-treatment benefit of switching to exemestane (HR, 0.60; 95% CI, 0.48 to 0.75; P < .001) was not lost post-treatment, but that there was no additional gain once treatment had ceased (HR, 0.94; 95% CI, 0.80 to 1.10; P = .60). Improvement in overall survival was demonstrated, with 352 deaths in the exemestane group versus 405 deaths in the tamoxifen group (HR, 0.86; 95% CI, 0.75 to 0.99; P = .04). Of these, 222 were reported as intercurrent deaths (exemestane, 107; tamoxifen, 115).CONCLUSION:The protective effect of switching to exemestane compared with continuing on tamoxifen on risk of relapse or death was maintained for at least 5 years post-treatment and was associated with a continuing beneficial impact on overall survival.

INTRODUCTION:For postmenopausal patients with hormone-sensitive breast cancer, outcome is worse with increasing age at diagnosis. The aim of this study was to assess the incidence of breast cancer recurrence (locoregional and distant), and contralateral breast cancer by age at diagnosis.METHODS:Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. Primary endpoints were locoregional recurrence, distant recurrence, and contralateral breast cancer. Age at diagnosis was categorized as younger than 65 years, 65-74 years, and 75 years or older.RESULTS:Overall, 9,766 patients were included, of which 5,349 were younger than 65 years (reference group), 3,060 were 65-74 years, and 1,357 were 75 years or older. With increasing age, a decreased administration of radiotherapy after breast conserving surgery (94%, 92%, and 88%, respectively) and adjuvant chemotherapy (51%, 23%, and 5%, respectively) was observed. Risk of distant recurrence increased with age at diagnosis; multivariable hazard ratio for patients aged 65-74 years was 1.20 (95% confidence interval [CI]: 1.00-1.44), hazard ratio for patients aged 75 years or older was 1.39 (95% CI: 1.08-1.79). Risks of locoregional recurrence and contralateral breast cancer were not significantly different across age groups.CONCLUSION:Elderly patients with breast cancer were at increased risk for distant recurrence. Other studies have shown that the risk of distant recurrence is mainly affected by adjuvant systemic therapy. All TEAM patients received adjuvant endocrine treatment; however, chemotherapy was administered less often in elderly patients. These findings are suggestive for consideration of chemotherapy in relatively fit elderly breast cancer patients with hormone-sensitive disease.