Distant Recurrence-free Interval Research Articles

Abstract S3-02: NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide (AC) in patients (pts) with node-negative breast cancer

Abstract Background NSABP B-36 was originally designed as a 2X2 factorial randomized study to compare 6 cycles of FEC-100 with 4 cycles of standard AC with or without celecoxib in pts with node-negative breast cancer. The rationale for the trial was based on observations from other adjuvant trials suggesting that longer duration of anthracycline-based therapy may result in improved outcomes and also on accumulating evidence that prostaglandins may contribute to the malignant phenotype in breast cancer. The trial opened in May 2004 but random assignment to celecoxib v placebo was terminated in December 2004 (after 327 pts were enrolled) because of concerns for increased risk of cardiovascular disease with the use of COX-2 inhibitors. The trial continued as a two-arm study and completed accrual in July 2008. The primary endpoint of disease-free survival (DFS), and secondary endpoints of overall survival (OS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), and adverse events comparing FEC-100 and AC are reported here. Analyses of quality of life indicators will be reported separately. Methods 2,722 pts with T1-3, pN0 breast cancer were randomly assigned to either adriamycin 60 mg/m2 and cyclophosphamide 600mg/m2 every 21 days for 4 cycles (n=1361) or 5-FU 500mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days for 6 cycles (n=1361). Hormone- receptor positive pts were to receive physician's choice of hormonal therapy for a minimum of 5 yrs. Trastuzumab for HER2-positive pts was at investigator's discretion but was not to begin for >3 weeks after the last dose of chemotherapy. All women treated with lumpectomy were to receive breast radiotherapy; post-mastectomy chest wall radiotherapy was at physician's discretion. The differences in DFS (OS, RFI, and DRFI) between two treatment arms were assessed by log-rank test stratified by hormone receptor status and type of surgery. Results Median follow-up is 82.8 months. Pt and tumor characteristics were equally distributed between the two groups (<50 years old: 40%, lumpectomy: 68%, and hormone positivity: 65 %). Overall, Grade 3 and 4 expected toxicities were more frequent in the FEC arm. Combined Grade 3/4 toxicities reaching statistical significance with a difference of 3% or more between AC and FEC arms included fatigue 3.55% v 8.45%, febrile neutropenia 3.70% v 9.42%, and thrombocytopenia 0.74% v 4.41%, respectively. While on treatment, Grade 3 left ventricular systolic dysfunction occurred in one pt in each arm. There were 2 toxicity deaths on AC and 5 on the FEC arm. Primary and secondary endpoint analyses at 8 ys did not reveal any significant differences in DFS, OS, RFI, or DRFI. EndpointAC (%)FEC (%)HRCIp-valueDFS83.082.81.040.85,1.260.70OS91.292.00.940.71,1.240.65RFI90.090.40.970.76,1.260.84DRFI92.393.00.890.66,1.200.43 Conclusions Six cycles of the FEC-100 regimen did not result in any efficacy advantage over 4 cycles of standard AC in node-negative breast cancer pts. As anticipated, the FEC-100 regimen resulted in greater toxicity. Support NCI: U10-CA-12027, -37377, -69974, -69651, -44066-26; Pharmacia & Upjohn Co. Citation Format: Jacobs A Samuel, John W Wilson, Hanna Bandos, Richard M Elledge, André Robidoux, Louis Fehrenbacher, Patrick J Ward, Johnathan Polikoff, Adam M Brufsky, Louise Provencher, Alexander HG Paterson, John T Hamm, Robert L Carolla, Luis Baez-Diaz, Priya Rastogi, Thomas B Julian, D Lawrence Wickerham, Sandra M Swain, Charles E Geyer Jr, Eleftherios P Mamounas, Norman Wolmark. NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide (AC) in patients (pts) with node-negative breast cancer [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 S3-02.

Abstract P3-12-01: Impact of treatment on quality of life (QOL) and menstrual history (MH) in the NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide

Abstract Background NSABP B-36 compares 6 cycles of FEC-100 with 4 cycles of standard AC in pts with node-negative breast cancer. As reported separately, no significant differences between the two treatment arms were observed in the primary endpoint of disease-free survival or in the secondary endpoints of overall survival, recurrence-free, or distant recurrence-free intervals. Greater toxicity was reported in pts who received FEC compared to AC. We present here the results of the QOL and MH studies obtained prospectively in conjunction with the treatment study. We hypothesized that pts on FEC would experience greater treatment toxicity in the first 12 months of the study, and would have greater rates of amenorrhea at 18 months compared to pts on AC. Methods Among the 1,357 pts enrolled in the QOL study, 1,332 (675 AC, 657 FEC) submitted the baseline form and had QOL follow-up (fup) information. Pts completed: 1) the FACT-B instrument; 2) a symptom checklist; and 3) the SF-36 Vitality Scale, all at baseline, day 1 of cycle 4, and at 6, 12, 18, 24, 30, and 36 months after random assignment. FACT-B Trial Outcome Index (TOI), symptom severity, and vitality scores were compared between the two treatment arms using a mixed model for repeated measures analysis with adjustment for the baseline scores, type of surgery, and hormone receptor status, examining the first 12 months and the later time points separately. Menstrual status was collected at baseline for all enrolled pts, with subsequent assessments on day 1 of cycle 4, and at 6, 12, 18, 24, 30, and 36 months for pts with menstrual bleeding within 12 months prior to random assignment and not having had a hysterectomy and/or bilateral oophorectomy (1, 096 pts). Post-chemotherapy amenorrhea was defined as the lack of menstrual periods during the 12 months preceding the 18-month fup evaluation. Data from 921 pts (475 AC, 446 FEC) were available for analysis. Logistic regression, adjusted for type of surgery and hormone receptor status, was used to test for association of amenorrhea status and treatment. Results Both TOI and vitality scores were worse for pts on FEC compared to those on AC at 6 months (p<0.01) with no significant difference at 12 months and beyond. No significant differences in symptom severity between the two treatment arms were observed. The rates of post-chemotherapy amenorrhea were significantly different between FEC and AC (66.8% vs. 58.7%, p=0.01) with positive hormone receptor status as an independent risk factor (p=0.03). Conclusions Women receiving FEC had diminished QOL at 6 months after random assignment, but no difference at 12 months or later. Premenopausal women receiving FEC experienced a higher rate of post-chemotherapy amenorrhea than women receiving AC. Support NCI grants U10-CA-12027, -37377, -69974, -69651 and -44066-26, and Pharmacia & Upjohn Company, a subsidiary of Pfizer, Inc. Citation Format: Patricia A Ganz, John W Wilson, Hanna Bandos, André Robidoux, Alexander HG Paterson, Johnathan Polikoff, Luis Baez-Diaz, Adam M Brufsky, Louis Fehrenbacher, Aroop Mangalik, Patrick J Ward, Louise Provencher, John T Hamm, Philip J Stella, Robert L Carolla, Richard G Margolese, Henry R Shibata, Edith A Perez, Norman Wolmark. Impact of treatment on quality of life (QOL) and menstrual history (MH) in the NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide [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 P3-12-01.

Tumour size is the only predictive factor of distant recurrence after pathological complete response to neoadjuvant chemotherapy in patients with large operable or locally advanced breast cancers: A sub-study of EORTC 10994/BIG 1-00 phase III trial

PurposeAlthough achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in breast cancer predicts a better outcome, some patients still relapse. The objectives of this study were to describe the types of events in this group of patients and to identify predictive factors for relapse. MethodsPatients with large operable or locally advanced breast cancers (T4d tumours were excluded) were randomised to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel followed by three cycles of eprirubicin/docetaxel. pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in the primary tumour and axillary lymph nodes at surgery. Two Cox regression analyses were performed to identify predictive factors of relapse: one for recurrence-free interval (RFI) and one for distant recurrence-free interval (DRFI). ResultsOut of 283 eligible patients who achieved a pCR, 40 (14.1%) and 28 (9.9%) presented an event of interest for the RFI and DRFI analyses, respectively. Five-year RFI, DRFI and overall survival (OS) were 85.3% (95% confidence interval (CI), 80.1–89.3), 89.6% (95% CI, 85.0–92.9) and 91.9% (95% CI, 87.2–94.9), respectively. No predictors for RFI after pCR were identified. For DRFI, tumour size was the only predictor: Hazard ratio (HR) T3 versus T1–2=3.62 (95% CI, 1.66–7.89); HR T4 versus T1–2: HR, 2.80 (95% CI, 0.62–12.64) p=0.0048. ConclusionIn this study, clinical tumour size emerged as the only predictor for DRFI after pCR, with T3 and T4 tumours having an increased risk for distant recurrence compared to T1–2 tumours.

Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.

Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

174P - Prediction of Recurrence with the Recurrence Score in Pre- and Post-Menopausal Patients from the Pacs01 Trial

ABSTRACT Aim: The Recurrence Score (RS) predicts outcome in node- and node + , ER+ pts treated with endocrine therapy and chemotherapy (CT) benefit. We studied the prognostic impact of the RS in node + , HR+ pre and post-menopausal pts treated with adjuvant chemohormonal therapy in PACS01 and here present an analysis of the performance of the RS in pre- and post-menopausal pts. Methods: PACS01 compared FEC with FEC-D in 1999 pts. The current study included 530 pts from the PACS01 parent trial who were central IHC HR+ with sufficient tissue for Oncotype DX. Primary objective was to estimate the association between RS and distant recurrence free interval (DRFI). Secondary endpoints included disease free survival (DFS) and overall survival (OS). Herein we explore the association of the RS in pre- and post-menopausal women. Median follow-up time was 7.7 yrs. Results: Of 530 pts, 317 were pre-menopausal and 205 were post-menopausal - 209 (39.4%) had low; 159 (30.0%) intermediate; and 162 (30.6%) high RS. Of pre-menopausal, 124 (39.1%) had low; 89 (28.1%) intermediate & 104 (32.8%) high RS. Of post-menopausal 84 (41.0%) had low, 68 (33.2%) intermediate & 53 (25.9%) high RS. 74.2% were treated with tam. In the primary analysis, RS was a significant predictor of DRFI (HR= 4.1 for a 50 point difference, P RS Low RS Int RS High Log-rank p-value All pts n = 530 93.7 (89.4–96.3) 87.3 (81.0–91.6) 69.3 (61.5–75.8) p Pre-meno n = 317 93.5 (87.4–96.7) 89.8 (81.3–94.5) 70.9 (61.1–78.7) p Post-meno n = 205 94.0 (86.2–97.5) 85.2 (74.2–91.7) 64.9 (50.2–76.3) p Conclusions: The 21-gene RS was prognostic in HR + , node+ pts treated with FEC or FEC-D adjuvant CT and the performance was similar in pre- and post-menopausal pts. The data is consistent with those presented from B28 providing further supportive evidence for the assay's validity in pre-menopausal, node+ pts. Disclosure: F. Penault-Llorca: I have an advisory relationship with Genomic Health Inc, and receive speaker's honoraria from Genomic Health, Inc.; F. Baehner: Frederick Baehner is an employee of Genomic Health, Inc.; P. Fumoleau: Dr Fumoleau has an consultant/advisory relationship with Sanofi, Roche and Novartis. S. Butler: Mr. Butler is an employee of Genomic Health, Inc.; F. Jamshidian: Mr Jamshidian is an employee of Genomic Health, Inc.; D. Cherbavaz: Mrs Cherbavaz is an employee of Genomic Health, Inc. All other authors have declared no conflicts of interest.

Predictive and prognostic value of the 21-gene recurrence score in hormone receptor-positive, node-positive breast cancer.

The addition of adjuvant chemotherapy to hormonal therapy is recommended for patients with estrogen receptor–positive (ER+), node-positive (N+) early breast cancer (EBC). Some of these patients, however, are not likely to benefit from treatment and may, therefore, be overtreated while also incurring unnecessary treatment-related adverse events and health care costs. The 21-gene Recurrence Score assay has been clinically validated and recommended for use in patients with ER+, node-negative (N0) EBC to assess the 10-year risk of distant disease recurrence and predict the likelihood of response to adjuvant chemotherapy. A growing body of evidence from several large phase III clinical trials reports similar findings in patients with ER+, N+ EBC. A systematic review of published literature from key clinical trials that have used the 21-gene breast cancer assay in patients with ER+, N+ EBC was performed. The Recurrence Score has been shown to be an independent predictor of disease-free survival, overall survival, and distant recurrence-free interval in patients with ER+, N+ EBC. Outcomes from decision impact and health economics studies further indicate that the Recurrence Score affects physician treatment recommendations equally in patients with N+ or N0 disease. It also indicates that a reduction in Recurrence Score–directed chemotherapy is cost-effective. There is a large body of evidence to support the use of the 21-gene assay Recurrence Score in patients with N+ EBC. Use of this assay could help guide treatment decisions for patients who are most likely to receive benefit from chemotherapy.

Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials.

LBA1 Background: Adjuvant endocrine therapy with AI vs T improves outcomes in postmenopausal HR+ BC. TEXT and SOFT were designed to test whether adjuvant AI improves outcomes in premenopausal women with HR+ BC treated with OFS (AI question) and to determine the value of OFS in women who remain premenopausal and are suitable for adjuvant T (OFS question). Methods: TEXT and SOFT, randomized phase 3 trials, enrolled 5,738 premenopausal women with HR+ early BC from Nov03 to Apr11 (2672 TEXT; 3066 SOFT). TEXT randomized women within 12wk of surgery to 5y E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5y E+OFS vs T+OFS vs T alone, either within 12wk of surgery if no CT planned, or within 8mo of completing (neo)adjuvant CT. OFS was by choice of 5y triptorelin, oophorectomy, or ovarian irradiation. The primary endpoint is disease-free survival (DFS: randomization until invasive local, regional, distant recurrence, or contralateral breast; 2nd malignancy; death). Due to low event rates, protocol amendments in 2011 changed the analysis plans to answer the AI question (E+OFS vs T+OFS) by joint analysis of TEXT and SOFT. By Q3’2013 with >5y median follow-up, 436 DFS events were projected, providing 84% power for HR=0.75 with E+OFS vs T+OFS (stratified logrank 2-sided α=0.05). Results: At 5.7y median follow-up, 514 (11%) DFS events were reported in the ITT population comparing E+OFS (n=2346) vs T+OFS (n=2344). Patients assigned E+OFS had significantly reduced DFS hazard (HR=0.72; 95% CI, 0.60-0.86; P=0.0002) vs T+OFS; 5y DFS was 91.1% vs 87.3%. Reductions were similar for secondary endpoints of BC-free interval (HR=0.66 (0.55-0.80) 5y BCFI 92.8% vs 88.8%) and distant recurrence-free interval (HR=0.78 (0.62-0.97)), though not overall survival (HR=1.14 (0.86-1.51)) at this early follow-up (194 (4%) deaths). Grade 3-4 targeted AEs were reported in 31% E+OFS vs 29% T+OFS patients. Conclusion: In premenopausal women with HR+ BC, adjuvant treatment with E+OFS significantly reduced the risk of recurrence compared to T+OFS. Clinical trial information: NCT00066703 / NCT00066690 .

Optimized outcome prediction in breast cancer by combining the 70-gene signature with clinical risk prediction algorithms.

Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70-gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-014-2954-2) contains supplementary material, which is available to authorized users.

Abstract P6-06-13: Optimized prediction of clinical outcome by the PREDICT plus tool and the 70-gene signature in early stage node-negative breast cancer

Abstract Background Established breast cancer guidelines and online tools use clinico-pathological factors including age, tumor size and grade to evaluate the risk of recurrence and select patients who are eligible to receive adjuvant chemotherapy (ACT). One of the online tools, PREDICT plus, was recently updated and is the first tool to include HER2 status and method of detection in risk assessment. Another tool to better guide AST decisions is the 70-gene signature. The 70-gene signature is a gene-expression classifier that was developed and extensively validated to predict the risk of distant recurrence in breast cancer. In clinical practice, an ad-hoc combination of clinico-pathological guidelines and gene-expression classifiers are used. The aim of this study is to evaluate the combination of the PREDICT plus tool and the 70-gene signature to optimize adjuvant systemic treatment decisions. Methods For 427 patients participating in the RASTER study (cT1-3N0M0) a 70-gene signature result was available. PREDICT risk estimates at 5 (P5) and 10 (P10) years after diagnosis were calculated using the following variables: age, method of detection, tumor size, tumor grade, number of positive nodes, estrogen receptor, and HER2 status. Patients were considered high risk if their survival probability was less than 95% at 5 years and/or 90% at 10 years. Five-year distant-recurrence-free-interval (DRFI) and distant-disease-free-survival (DDFS) probabilities were evaluated between subgroups based on the 70-gene signature and PREDICT plus. Results Median follow-up was 61.6 months. Patients with a low risk 70-gene signature (n = 219) had a 5-year DRFI of 97.0% (CI: 94.7-99.4) compared to 91.7% (CI: 87.9-95.7) for the 70-gene signature high risk patients (n = 208). The 5-year DRFI for patients with a P5 low risk (n = 228) is 96.8% (CI: 94.2-99.4) compared to 91.7% (CI: 87.9-95.7) for P5 high risk (n = 199). The 5-year DRFI for patients with a P10 low risk (n = 168) is 98.0% (CI: 95.7-100) compared to 92.1% (CI: 88.7-95.6) for P10 high risk (n = 259). ACT data, DRFI and DDFS probabilities in all subgroups are shown in table 1. Among the patients who had a low risk according to PREDICT at 5 years, but a high risk at 10 years (n = 60), the 5-year DRFI was 100% when their tumor was tested as low risk based on the 70-gene signature (13% received CT) compared to 84% in case of a high risk result (55% received CT)(p = 0.03). Table 170-gene signatureP5P10ACT (%)5-year DRFI (%) (95% CI)5-years DDFS (%) (95% CI)LowLowLow8/132 (6)97 (94-100)96 (92-100)HighLowLow21/36 (59)10097 (92-100)LowHighLowxxxxxxxxxLowLowHigh5/38 (13)100100HighHighLowxxxxxxxxxHighLowHigh12/22 (55)84 (69-100)84 (69-100)LowHighHigh20/49 (41)94 (87-100)94 (87-100)HighHighHigh136/150 (91)91 (87-96)89 (84-94) Conclusion Combining PREDICT plus with the 70-gene signature may help to identify early stage node-negative breast cancer patients for whom limited adjuvant systemic treatment might be appropriate and for whom overtreatment can be avoided. Especially in case of a low risk assessment by PREDICT at 5 years but a high risk at 10 years, the 70-gene signature may aid to select those patients at a high risk of recurrence who will benefit most from ACT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-13.

Abstract OT1-1-06: A phase 3, randomized, open-label trial comparing trastuzumab emtansine and trastuzumab as adjuvant therapy for HER2-positive primary breast cancer with residual invasive tumor in the breast or axillary lymph nodes following preoperative therapy (KATHERINE)

Abstract Background: HER2-positive patients (pts) who do not achieve pathologic complete response with preoperative chemotherapy and HER2 directed therapy (PST) are at increased risk of recurrence and mortality despite further anti-HER2-targeted and endocrine treatment. The antibody–drug conjugate trastuzumab emtansine (T-DM1) combines the antitumor activities of trastuzumab (H) with intracellular delivery of the cytotoxic agent DM1 via a stable linker. T-DM1 prolonged progression-free survival (PFS) and overall survival (OS) in a phase 3 study in pts with previously treated HER2-positive metastatic breast cancer (MBC) compared with capecitabine and lapatinib. It also prolonged PFS compared with H and docetaxel in a phase 2 study in pts with previously untreated HER2-positive MBC. Trial design: KATHERINE (NCT01772472) is a phase 3, 2-arm, open-label trial in pts with HER2-positive primary breast cancer (BC) who have received PST, including H, and have residual invasive disease after surgery. Pts are randomly assigned 1:1 to adjuvant T-DM1 3.6 mg/kg IV q3w or H 6 mg/kg IV q3w for 14 cycles. Pts can receive concomitant radiotherapy and/or hormonal therapy if clinically indicated. Eligibility criteria: HER2-positive BC (centrally determined IHC 3+ and/or ISH ratio ≥2); clinical stage T1–4, N0–3, M0 (T1a/bN0 ineligible) prior to PST; ECOG PS 0 or 1; adequate surgical excision; ≥6 cycles of preoperative treatment (≥16 weeks total; ≥9 weeks of H and ≥9 weeks of taxane-based chemotherapy); residual invasive breast or axillary lymph node disease after preoperative therapy; ≤12 weeks from surgery to random assignment. Pts with anthracycline exposure equivalent to doxorubicin >240 mg/m2 or significant cardiopulmonary dysfunction are excluded. Specific aims: The primary efficacy endpoint is invasive disease-free survival (IDFS). Secondary endpoints include disease-free survival, OS, distant recurrence-free interval, quality of life, and pharmacokinetics. Safety assessments include all adverse events, abnormal laboratory values, cardiac events, and LVEF. Statistical methods: The log-rank test (stratified by clinical stage, hormone receptor status, preoperative HER2-directed therapy, and pathologic nodal status after preoperative therapy) will be used to compare IDFS between arms. The hazard ratio (HR) and its 95% confidence interval (CI) will be estimated using Cox proportional hazards model (also stratified). The Kaplan-Meier approach will be used to estimate 3-year IDFS rates and 95% CIs for each arm. The final IDFS analysis, which provides 80% power to detect a HR of 0.75 (a 6.5% improvement in 3-year IDFS from 70% in the control arm to 76.5% in the T-DM1 arm) at a 2-sided alpha level of 5%, will be performed after ∼384 IDFS events have occurred. The final OS analysis will be performed at the end of 10 years of follow-up. Interim analyses of IDFS and OS are planned. Current and target accrual: Enrollment to 342 sites in 28 countries began in April 2013, and target accrual is 1484 pts. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-06.

Abstract S1-03: Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer

Abstract Background The humanized monoclonal antibody (mAb) trastuzumab (H) + chemotherapy (chemo) prolongs disease-free survival (DFS) in patients (pts) with HER2-positive breast cancer (BC) in the adjuvant setting. Vascular endothelial growth factor (VEGF-A), one central regulator of angiogenesis, is a downstream target of HER2. Tumors overexpressing HER2 also overexpress VEGF-A and exhibit increased angiogenic potential. Combining H with the anti-VEGF-A mAb bevacizumab (B) significantly decreased tumor volume vs B or H alone in HER2-positive xenograft models and demonstrated efficacy in phase 2 studies. In the phase 3 AVEREL study in pts with HER2-positive metastatic BC, adding B to H + docetaxel (T) led to a non-significant increase in a duration of PFS and objective response rates. Chemo plus H±B is now explored in this large phase 3 trial to assess the impact of VEGF-A blockade on residual or micrometastatic disease in the adjuvant setting. Methods BETH (NCT00625898) is a randomized, phase 3, open-label study evaluating the addition of B to 2 different H-chemo regimens. Pts had centrally-confirmed HER2-positive BC (FISH+ and/or IHC 3+), ECOG PS 0-1, unilateral invasive breast adenocarcinoma, total mastectomy or lumpectomy, and LVEF ≥55%. Prior therapy with anthracyclines, taxanes, carboplatin (C), H or B for any malignancy or radiotherapy, chemo, and/or targeted therapy for the currently diagnosed BC were not permitted. Pts were stratified by center, hormone receptor status (ER and/or PR-positive, ER/PR-negative), and axillary lymph node status (0, 1-3, 4+) before inclusion into 1 of 2 chemo cohorts, and then randomized. All pts were recruited by investigators from the Translational Research in Oncology (TRIO/CIRG), the National Surgical Adjuvant Breast and Bowel Project (NSABP) or a group of independent sites. Cohort 1 (3231 pts) included pts receiving 6 cycles of TCH±B followed by H±B for 1 yr after the first dose. Cohort 2 (278 pts) included pts from some independent sites electing to use anthracycline-based therapy and these pts received 3 cycles of TH±B followed by 3 cycles of 5-fluorouracil, epirubicin, cyclophosphamide followed by H±B to complete 1 yr of treatment. T was given at 8 mg/kg IV loading dose, 6 mg/kg IV q3w thereafter; B was given at 15 mg/kg IV q3w. The primary endpoint is invasive DFS (IDFS) for B-containing vs. non-B-containing regimens. Secondary endpoints are IDFS within chemo cohorts, DFS, overall survival, recurrence-free interval (RFI), distant RFI, safety including specific cardiac assessments, and the identification of predictive biomarkers for B. The sample size was determined to test the hypothesis of interest, both in the faster accruing cohort and overall. With 3509 pts enrolled, the trial will have 85% power to detect a HR of 0.70 favoring the addition of B overall, irrespective of chemo regimen. With ∼3000 pts in the faster-accruing cohort, the study will have 80% power to detect a hazard ratio (HR) of 0.70 at a 2-sided alpha of 0.05. Median duration of follow-up will be 36 months in Jun 13, cut-off date of the primary analysis. Initial efficacy, safety, and plasma marker analyses will be reported. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-03.

Radiofrequency ablation of metastatic liver masses: recurrence patterns and prognostic factors based on radiologic features.

To investigate the therapeutic result of RFA and the factors predicting recurrence after RFA in patients with hepatic metastases. We reviewed 33 patients who had hepatic metastases and underwent curative RFA. Statistical analysis of the determinants of tumor recurrence was done by sex, age, site and differentiation of the primary cancer, lesion size, location within the liver, ablative margin and presence of vessels contiguous to the mass and time from the initial liver metastasis to RFA. Marginal tumor recurrence was seen at the ablation margin in 13 (25%) of 52 lesions. Lesions with an ablative margin of 5mm or more had longer marginal recurrence-free interval compared to lesions with an ablative margin of less than 5mm. The patients with primary colorectal cancer had a significantly longer distant recurrence-free interval compared to patients with non-colorectal neoplasms. Percutaneous RFA is an effective alternative modality for the treatment of hepatic metastases from various primary cancers and has a relatively low recurrence rate. The presence of an ablative margin was a significant prognostic factor for marginal tumor recurrence. In addition, distant metastasis, a new hepatic lesion or extrahepatic was significantly influenced by the site of the primary cancer.

A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study

The 70-gene signature (MammaPrint™) has been developed on retrospective series of breast cancer patients to predict the risk of breast cancer distant metastases. The microarRAy-prognoSTics-in-breast-cancER (RASTER) study was the first study designed to prospectively evaluate the performance of the 70-gene signature, which result was available for 427 patients (cT1–3N0M0). Adjuvant systemic treatment decisions were based on the Dutch CBO 2004 guidelines, the 70-gene signature and doctors' and patients' preferences. Five-year distant-recurrence-free-interval (DRFI) probabilities were compared between subgroups based on the 70-gene signature and Adjuvant! Online (AOL) (10-year survival probability <90% was defined as high-risk). Median follow-up was 61.6 months. Fifteen percent (33/219) of the 70-gene signature low-risk patients received adjuvant chemotherapy (ACT) versus 81% (169/208) of the 70-gene signature high-risk patients. The 5-year DRFI probabilities for 70-gene signature low-risk (n = 219) and high-risk (n = 208) patients were 97.0% and 91.7%. The 5-year DRFI probabilities for AOL low-risk (n = 132) and high-risk (n = 295) patients were 96.7% and 93.4%. For 70-gene signature low-risk–AOL high-risk patients (n = 124), of whom 76% (n = 94) had not received ACT, 5-year DRFI was 98.4%. In the AOL high-risk group, 32% (94/295) less patients would be eligible to receive ACT if the 70-gene signature was used. In this prospective community-based observational study, the 5-year DRFI probabilities confirmed the additional prognostic value of the 70-gene signature to clinicopathological risk estimations such as AOL. Omission of adjuvant chemotherapy as judged appropriate by doctors and patients and instigated by a low-risk 70-gene signature result, appeared not to compromise outcome.

Abstract S4-4: Independent validation of Genomic Grade in the BIG 1-98 study

Abstract Background: We have reported that a 97-gene signature, the Genomic Grade Index (GGI) can separate histological grade (HG) 2 breast tumors into low vs high GGI tumors with different outcomes. We have also developed a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) tool including 6 reporter and 3 control genes that can reliably evaluate Genomic Grade (GG) in paraffin embedded tumors. Methods: We evaluated the qRT-PCR GG in women treated with either tamoxifen or letrozole monotherapy in the Breast International Group (BIG) 1–98 study with 8.1 year median follow-up. The association between continuous GG and distant recurrence-free interval (DRFI) was evaluated in Cox regression models stratified for the 2 vs 4 arm randomization option, chemotherapy and hormonotherapy use, with and without adjustment for clinicopathological characteristics. Estrogen, progesterone receptor (ER, PR), Ki67 and HG were centrally reviewed. The clinicopathological model included age and log2 tumor size, ER and PR as continuous variables, nodal status (N0 vs 1–3 vs &amp;gt;3), HG (1 vs 2 vs 3) and HER2 (negative vs positive). Similar analyses were performed for log2 Ki67 as continuous variable. Added prognostic value was assessed using the likelihood ratio statistic. Results: We obtained GG in 883 (62%) of 1428 samples. Non evaluable results were due to pre-analytical issues or technical failure. Among the 883 patients, 521 (59%) had N0 disease, 435 (49%) were treated with tamoxifen and 84 (10%) had distant recurrences. The GG classified 502 patients with HG2 tumors as either GG1 (N = 202, 40%), equivocal (N = 220, 44%) or GG3 (N = 80, 16%). In univariate analysis, increasing GG and Ki67 were significantly associated with lower DRFI (Table). When the 773 N0/1-3 patients were analyzed based on HG, the Kaplan-Meier estimate for 10-year DRFI was 98% (95% confidence intervals 96–100%) for the 123 HG1, 92% (88–95%) for the 456 HG2 and 84% (78–90%) for the 194 HG3 patients. In the N0/1-3 population, 10 year DRFI based on GG was 95% (96–100%) for the 290 GG1, 92% (89–95%) for the 309 GG equivocal and 84% (77–90%) for the 178 GG3 patients. Interestingly, when the 456 HG2 and N0/1-3 patients were analyzed based on GG, the 10-year DRFI was 95% (92–100%) for the 185 HG2/GG1 patients, 92% (88–96%) for the 202 HG2/GG equivocal patients, 86% (76–96%) for the 69 HG2/GG3 patients. In all patients either GG or Ki67 as continuous variable significantly improved the clinicopathological model in predicting distant recurrence (Table). Conclusion: Either Genomic Grade or centrally reviewed Ki67 provides independent prognostic information for risk of distant recurrence beyond clinicopathological characteristics in patients treated with endocrine therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-4.

Abstract P6-07-34: Disease-related outcomes with adjuvant chemotherapy in HER2 positive or triple negative T1a/bN0 breast cancers

Abstract Background: Previous studies reported higher relapse rates in T1a/bN0 breast cancers characterized by high-risk biology (HER2 positive or triple negative). The benefits of adjuvant chemotherapy in this group have not been evaluated. The purpose of our study was to determine potential impact of chemotherapy on incidence of relapses and to define the population appropriate for treatment based on observational data. Methods: We pooled data from two multi-institutional databases spanning the period of 1996–2008 (Beth Israel Medical Center) and 2000–2010 (Brown University). We fitted a propensity score model to adjust for unbalanced confounders between the groups treated or untreated with adjuvant chemotherapy and, in case of HER2+ disease, with trastuzumab. Competing risk analysis was employed to study the effect of chemotherapy on cancer relapses in the matched population. Results: The study included 321 patients (160 from Beth Israel and 161 from Brown) with a median age of 57 years (range 28–88). 111 (35%) cases were triple negative (TN) and 210 (65%) were HER2+ (of which 64% were ER+). 41% patients received adjuvant chemotherapy and 22% of HER2+ cases received trastuzumab. The treated group differed from untreated with regards to distribution of age, menopausal status, year of diagnosis, histological subtype and grade, tumor size, rates of mastectomy, and adjuvant endocrine therapy. All confounders were successfully balanced with the propensity score analysis. With a median follow-up of 56 months, 20 relapses (12 locoregional and 8 distant) and 10 unrelated deaths occurred. The cumulative incidence of relapse at 5 years was 7.3% (95% CI, 4.3–11.4) and relapse-free survival was 90.2% (95% CI, 85.2–93.6). Age less then 35 years (46.4% vs. 6.1%, p = 0.0004) and TN status (12.9% for TN versus 4.8% for HER2+, p = 0.03) were associated with higher risk of relapse. No significant differences with regards to tumor size (T1a or T1b), surgery type and other variables were observed. There was no significant effect of chemotherapy on incidence of relapse (Hazard ratio 1.2, 95% CI 0.34–4.23, p = 0.78), relapse-free survival or distant recurrence-free interval after propensity score adjustment. Additionally in the HER2+ patients, no benefit of trastuzumab was detected (hazard ratio 0.78, 95% CI 0.06–9.85, p = 0.85). Adjuvant endocrine therapy was associated with lower risk of relapse in the ER+ subgroup (p = 0.04). Conclusion: Survival outcomes in very early stage breast cancer are excellent with current therapy even in biologically aggressive subtypes. Triple negative status and very young age correlate with higher incidence of relapse. While adjuvant endocrine therapy may be effective in ER positive subset, the risk/benefit ratio of chemotherapy with or without trastuzumab remains uncertain. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-34.

Prognosis of medullary breast cancer: analysis of 13 International Breast Cancer Study Group (IBCSG) trials

To evaluate whether medullary breast cancer has a better prognosis compared with invasive ductal tumors. Among 12,409 patients, 127 were recorded as invasive medullary tumors and 8096 invasive ductal tumors. Medullary and ductal invasive tumors were compared with regard to stage, age at diagnosis, grade, hormone receptor status, peritumoral vascular invasion, and local and systemic treatment. Pattern of relapse, distant recurrence-free interval (DRFI), and overall survival (OS) were determined for both histological groups. Two cohorts were investigated: a full cohort including the pathologist-determined medullary histology without regard to any other tumor features and a cohort restricted to patients with ER-negative grade 3 tumors. Fourteen-year DRFI and OS percents for medullary tumors (n = 127) and invasive ductal tumors (n = 8096) of the full cohort were 76% and 64% [hazard ratio (HR) 0.52, P = 0.0005] and 66% and 57% (HR = 0.75, P = 0.03), respectively. For the restricted cohort, 14-year DRFI and OS percents for the medullary (n = 47) and invasive ductal tumors (n = 1407) were 89% and 63% (HR 0.24, P = 0.002) and 74% and 54% (HR = 0.55, P = 0.01), respectively. Competing risk analysis for DRFI favored medullary tumors (HR medullary/ductal = 0.32; 95% confidence interval = 0.13-0.78, P = 0.01). Medullary tumors have a favorable prognosis compared with invasive ductal tumors.

Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy

AbstractBACKGROUND:Population‐based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy.METHODS:Adjuvant chemotherapy trials coordinated by the Eastern Cooperative Oncology Group that accrued patients between 1978 and 2002 were reviewed. Survival after distant disease recurrence was estimated for progressive time periods, and adjusted for baseline covariates in a Cox proportional hazards model.RESULTS:Of the 13,785 patients who received adjuvant chemotherapy in 11 trials, 3447 (25%) developed distant disease recurrence; the median survival after recurrence was 20 months (95% confidence interval, 19 months‐21 months). Factors associated with inferior survival included a shorter distant recurrence‐free interval (DRFI), estrogen receptor‐negative and progesterone receptor‐negative disease, the number of positive axillary lymph nodes present at the time of diagnosis, and black race (P &lt; .0001 for all). When the time period of recurrence was added to the model, it was not found to be significantly associated with survival for the general population with disease recurrence. Survival improved over time only in those patients with hormone receptor‐negative disease with a DRFI ≤ 3 years, both among the 5 most recent and the entire trial data sets (P = .01 and P = .05, respectively).CONCLUSIONS:In contrast to reports from population‐based studies, no general improvement in survival was observed over the last 30 years for patients who developed distant disease recurrence after adjuvant chemotherapy after adjusting for DRFI. Improved survival for patients with hormone receptor‐negative disease with a short DRFI suggests a benefit from trastuzumab. Cancer 2013. © 2012 American Cancer Society.

Obesity and Risk of Recurrence or Death After Adjuvant Endocrine Therapy With Letrozole or Tamoxifen in the Breast International Group 1-98 Trial

To examine the association of baseline body mass index (BMI) with the risk of recurrence or death in postmenopausal women with early-stage breast cancer receiving adjuvant tamoxifen or letrozole in the Breast International Group (BIG) 1-98 trial at 8.7 years of median follow-up. This report analyzes 4,760 patients with breast cancer randomly assigned to 5 years of monotherapy with letrozole or tamoxifen in the BIG 1-98 trial with available information on BMI at randomization. Multivariable Cox modeling assessed the association of BMI with disease-free survival, overall survival (OS), breast cancer-free interval, and distant recurrence-free interval and tested for treatment-by-BMI interaction. Median follow-up was 8.7 years. Seventeen percent of patients have died. Obese patients (BMI ≥ 30 kg/m(2)) had slightly poorer OS (hazard ratio [HR] = 1.19; 95% CI, 0.99 to 1.44) than patients with normal BMI (< 25 kg/m(2)), whereas no trend in OS was observed in overweight (BMI 25 to < 30 kg/m(2)) versus normal-weight patients (HR = 1.02; 95% CI, 0.86 to 1.20). Treatment-by-BMI interactions were not statistically significant. The HRs for OS comparing obese versus normal BMI were HR = 1.22 (95% CI, 0.93 to 1.60) and HR = 1.18 (95% CI, 0.91 to 1.52) in the letrozole and tamoxifen groups, respectively. There was no evidence that the benefit of letrozole over tamoxifen differed according to patients' BMI.

Prognostic impact of the 21-gene recurrence score (RS) on disease-free and overall survival of node-positive, ER-positive breast cancer patients (pts) treated with adjuvant chemotherapy: Results from NSABP B-28.

1 Background: RS predicts outcome in node- and node+, ER+ pts treated with adjuvant endocrine therapy as well as benefit from adjuvant chemotherapy, with high RS receiving most of the benefit. We studied the prognostic impact of RS in node+, ER+ pts treated with adjuvant chemotherapy plus endocrine therapy as part of the NSABP B-28 trial. Methods: B-28 compared doxorubicin/cyclophosphamide (ACX4) with ACX4 followed by paclitaxel X4. Pts &gt;50 yrs and those&lt;50 yrs with ER+ and/or PR+ tumors also received 5 yrs of tamoxifen concurrently with chemotherapy. Between 8/95 and 5/98 3060 pts were accrued. The present study includes 1,065 pts ER+ by central tissue microarray IHC assay, tamoxifen treated, assessed by RS. Median follow-up time was 11.2 yrs. Results: Of the 1,065 pts, 386 (36%) had low RS&lt;18; 364 (34%) intermediate RS,18-30; and 315 (30%) high RS≥31. In univariate analyses RS was a significant predictor of DFS, distant recurrence-free interval (DRFI) and OS (Table). In multivariate analyses, RS provided independent prognostic information for all three endpoints beyond clinical and pathologic factors, e.g., treatment, age, tumor size, tumor grade, number of + nodes and type of surgery (p&lt;0.001). Conclusions: The 21-gene RS maintains significant prognostic impact in ER+, node+ pts who have received anthracycline- or anthracycline/taxane-based adjuvant chemotherapy. These findings emphasize the need to target pts with high residual risk for recurrence with additional therapies to overcome unfavorable biology, potential endocrine and/or chemotherapy resistance. Supported by: NCI, HHS, PHS, grants U10-CA-12027, -69651, -37377, -69974, and U24-CA-114732, and grants from Susan G. Komen for the Cure and Bristol-Myers Squibb Pharmaceutical Research Institute. [Table: see text]

OT1-02-04: Adjuvant Pertuzumab and Herceptin IN IniTial TherapY of Breast Cancer: APHINITY (BIG 4–11/BO25126/TOC4939g).

Abstract Background Approximately 20% of breast cancer (BC) patients (pts) have HER2−positive tumors. While the adjuvant use of the anti-HER2 humanized monoclonal antibody trastuzumab (T) has been shown to improve disease-free (DFS) and overall survival (OS), not all pts treated with this agent benefit from this therapy. Pertuzumab (P) is a humanized monoclonal antibody that inhibits HER2 dimerization and induces ADCC with a complementary mechanism of action to T. In HER2−positiveadvanced BC, T and P is active in pts who have progressed to T. In the neoadjuvant setting, T and P in combination with chemotherapy (CT) nearly doubled the pathological complete response rate compared to either T or P administered in combination with CT (45.8% vs 29% vs 24%, respectively). Therefore, comprehensive HER2 blockade with two anti-HER2 monoclonal antibodies warrants further investigation in the adjuvant setting. Trial Design: APHINITY is a prospective, randomized, multicenter, double-blind, placebo-controlled study in pts with HER2−positive primary BC who have had an excision of their tumor. Pts will be randomized to one of 2 arms (1:1 ratio). The investigational arm will comprise of a course of adjuvant CT (investigators choice) consisting of either an anthracycline-taxane or taxane-platin containing regimens and T and P for 1 year. The comparator arm will consist of the same adjuvant CT backbone with T and placebo for 1 year. Major Eligibility Criteria: 1. Non-metastatic primary BC histologically confirmed and adequately excised 2. Node-positive or node-negative: for patients with node-positive disease (pN ≥1), any pT except T0; for patients with node-negative disease (pN0), tumor size must be &amp;gt;1.0 cm OR for tumor size between &amp;gt;0.5 cm and ≤1.0 cm, at least one of the following features will be required: histologic grade 3 OR negative for ER and PgR OR age &amp;lt;35 years 3. The interval between definitive surgery for BC and randomization must be at least 3 weeks but no more than 7 weeks 4. Baseline LVEF ≥55% 5. HER2−positive BC confirmed by a central laboratory and defined as: IHC 3+ in &amp;gt;10% immunoreactive cells OR HER2 gene amplification by in situ hybridization [ISH] (ratio of HER2 gene signals to centromere 17 signals ≥2) Aims: The primary objective is to compare invasive disease-free survival (IDFS) between both treatment arms. Secondary objectives include comparing IDFS including second non-BC, DFS, OS, recurrence-free interval (RFI), distant RFI, cardiac safety, overall safety and health-related quality of life in the two treatment arms. Statistical Methods: Pts will be stratified based on nodal status, type of adjuvant CT regimen, hormone receptor status and geographical region. The study is designed to have an 80% power to test the null hypothesis of no true difference in risk of an IDFS event (HR = 1) versus the alternative hypothesis of a difference (HR = 0.75) in hazard rates with a 5%, 2-sided significance level. Target accrual: 3806; Present accrual: Start Q4 2011 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-02-04.