Search

Summary Background The goals of axillary-lymph-node dissection (ALND) are to maximise survival, provide regional control, and stage the patient. However, this technique has substantial side-effects. The purpose of the B-32 trial is to establish whether sentinel-lymph-node (SLN) resection can achieve the same therapeutic goals as conventional ALND but with decreased side-effects. The aim of this paper is to report the technical success and accuracy of SLN resection plus ALND versus SLN resection alone. Methods 5611 women with invasive breast cancer were randomly assigned to receive either SLN resection followed by immediate conventional ALND (n=2807; group 1) or SLN resection without ALND if SLNs were negative on intraoperative cytology and histological examination (n=2804; group 2) in the B-32 trial. Patients in group 2 underwent ALND if no SLNs were identified or if one or more SLNs were positive on intraoperative cytology or subsequent histological examination. Primary endpoints, including survival, regional control, and morbidity, will be reported later. Secondary endpoints are accuracy and technical success and are reported here. This trial is registered with the Clinical Trial registry, number NCT00003830. Findings Data for technical success were available for 5536 of 5611 patients; 75 declined protocol treatment, had no SLNs removed, or had no SLN resection done. SLNs were successfully removed in 97·2% of patients (5379 of 5536) in both groups combined. Identification of a preincision hot spot was associated with greater SLN removal (98·9% [5072 of 5128]). Only 1·4% (189 of 13171) of SLN specimens were outside of axillary levels I and II. 65·1% (8571 of 13 171) of SLN specimens were both radioactive and blue; a small percentage was identified by palpation only (3·9% [515 of 13 171]). The overall accuracy of SLN resection in patients in group 1 was 97·1% (2544 of 2619; 95% CI 96·4–97·7), with a false-negative rate of 9·8% (75 of 766; 95% CI 7·8–12·2). Differences in tumour location, type of biopsy, and number of SLNs removed significantly affected the false-negative rate. Allergic reactions related to blue dye occurred in 0·7% (37 of 5588) of patients with data on toxic effects. Interpretation The findings reported here indicate excellent balance in clinical patient characteristics between the two randomised groups and that the success of SLN resection was high. These findings are important because the B-32 trial is the only trial of sufficient size to provide definitive information related to the primary outcome measures of survival and regional control. Removal of more than one SLN and avoidance of excisional biopsy are important variables in reducing the false-negative rate.

121 Background: Breast cancer pathological complete response (pCR) following neoadjuvant therapy (NAT) is associated with better survival in some tumor subtypes. There is interest in identifying methods to increase early prediction of pCR during NAT. A simple and inexpensive technique such as early clinical breast examination has been shown to correlate with pCR during NAT in some studies. However, the optimal timing of the measurement and the best tumor response (TR) rate to predict pCR still need to be defined. Methods: We conducted a retrospective cohort study of patients prospectively enrolled in the following NSABP trials in one academic center (Montreal, Canada): B-40, B-41, FB-AX-003, FB-4, FB-5 and FB-6. Patients with T4 disease or disease progression were excluded. Clinical tumor measurements were recorded before each cycle of NAT. TR was measured as the percentage decrease in the largest tumor diameter. ROC curves for TR measurements at each time point were generated, comparing areas under the curve using the DeLong method. P-value ² 0.05 was considered significant. Results: We analyzed data of 155 patients recruited from Aug. 2005 to May 2011. Results are presented in Table 1. The best time point to predict pCR was after cycle 2. At this time point, a TR of 46% was the best cutoff value to predict for pCR. Among hormone receptor positive (HR+) and HER-2 positive (HER-2+) breast cancer patients, a TR of 47% after cycle 2 was significantly predictive for pCR. These findings were similar using a 50% TR cutoff after 2 cycles. Conclusions: Observing a 50% reduction in largest tumour diameter on clinical breast examination after cycle 2 of NAT is predictive for pCR in HR+ and HER-2+ breast cancer patients. We recommend using this definition of clinical response in future trials evaluating novel methods to improve early prediction of pCR during NAT. [Table: see text]

Background: Triple negative breast cancer (TNBC) is characterized by its aggressive phenotype and its genomic instability. TNBC patients who do not respond to neoadjuvant chemotherapy have a very poor prognosis. Currently, little is known about the mechanisms of drug resistance and how to overcome it in TNBC. Our study aims at identifying molecular factors enriched for in residual TNBC tumors after standard neoadjuvant chemotherapy. Methods: We obtained specimens from 60 TNBC patients participating in a clinical trial (Q-CROC-03). Biopsies were collected prior to and after standard neoadjuvant chemotherapy and residual cancer was collected at the time of surgery. Matched tumor specimens (pre and post) from 9 patients were analyzed by array comparative genomic hybridization (CGH), gene expression microarrays and whole exome sequencing. All samples contained >50% tumor cellularity. Results: Gene expression data was used to identify the different TNBC subtypes (TNBCtype). Six of the 7 subtypes were represented in at least one sample from our cohort. In the post-chemo samples, we observed a change in TNBC subtype compared to the pre-chemo samples in 6 pairs. The most common switch was to the Immuno Modulatory subtype (IM). aCGH analysis showed relatively few differences in copy number variants (CNV) following chemotherapy in 3 out of 8 patients. Whole exome sequencing revealed increased allele frequency or appearance of de novo mutations in TP53 gene in the residual cancers of 2 of the 3 patients presenting differences in CNVs post treatment. Interestingly, pathway analyses revealed that genes involved in DNA binding, chromosomal organization and nucleosome organization were differentially expressed (>2fold) in 2 of the patients with CNV changes. Our results suggest that increased levels of TP53 mutations and altered transcriptional expression of genes involved in chromosomal functions could be associated with the presence of CNV changes in drug resistant tumors. Conclusion: In summary, the genome of TNBCs does not undergo major changes during neoadjuvant chemotherapy; however, enrichment for or de novo TP53 mutations is associated with the appearance of novel CNVs in drug resistant residual tumors. Citation Format: Adriana Aguilar-Mahecha, Ewa Przybytkowski, Josiane Lafleur, Cathy Lan, Stephanie Légaré, Najmeh Alirezaie, Carole Séguin, Federico Discepola, Bojan Kovacina, Catalin Mihalcioiu, André Robidoux, Elizabeth Marcus, Josée Anne Roy, Manuela Pelmus, Olga Aleynikova, Sheida Nabavi, Jacek Majewski, Mark Basik. Genomic change in residual triple-negative breast cancers after neoadjuvant chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4320. doi:10.1158/1538-7445.AM2015-4320

1500 Background: NSABP P-2 (STAR) was a randomized, double-blinded trial of tamoxifen vs raloxifene for the reduction of breast cancer incidence. The initial report from 2006 found raloxifene to be...

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 ( 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.

Purpose The NSABP B-40 study was designed to determine whether the addition of capecitabine (X) or gemcitabine (G) to neoadjuvant docetaxel (T) followed by AC increased pathologic complete response (pCR) rates and improved outcomes of women with operable, HER2-negative breast cancer. In addition, B-40 was to determine whether the addition of neoadjuvant plus adjuvant bevacizumab (Bev) to T-based regimens followed by AC would increase pCR and improve outcomes. The pCR results and toxicities have been reported previously. The DFS and OS results are reported here for the first time. Methods Patients (Pts) received one of three T-based regimens for 4 cycles: T 100 mg/m2 day 1; T 75 mg/m2 day 1 and X 825 mg/m2 BID days 1-14; or T 75 mg/m2 day 1 and G 1000 mg/m2 days 1 and 8. Pts then received preoperative AC x 4 cycles. Pts randomly assigned to the Bev groups received Bev at 15mg/kg, q3wks x 6 with the first 6 courses of neoadjuvant chemotherapy and were to resume Bev post-operatively for 10 doses. 1,206 pts were assigned and 1,163 of them were clinically eligible and had follow-up. The cutoff date for data presented here was March 31, 2014. The median follow-up was 4.7 years. Results Neither X nor G added to neoadjuvant chemotherapy increased DFS or OS. 50% of Bev pts for whom treatment data were available (577) completed 10 doses of post-op Bev; 26% did not start Bev post-op. Addition of Bev significantly increased OS (HR=0.70, p=0.01) and marginally increased DFS (HR=0.81, p=0.06). The effect of Bev was most notable in women with hormone receptor positive (HR+) breast cancers (DFS HR=0.71, p=0.04; OS HR=0.63, p=0.03). Conclusions Addition of G or X to neoadjuvant T + AC had no significant impact on DFS or OS. Bev added to neoadjuvant chemotherapy and continued post-operatively marginally increased DFS in the overall cohort, with a significant increase in DFS in the HR+ subset. The addition of bevacizumab significantly improved OS for women with operable HER-2-negative breast cancer. In agreement with previously reported results for pCR, the improvement in DFS and OS was seen preferentially in women with HR+ breast cancers. Support NCI PHS grants U10-CA-37377, -69974, -12027, -69651, -44066, and -44066-26, Genentech Inc, Roche Laboratories Inc, Eli Lilly, and Precision Therapeutics, Inc. Citation Format: Harry D Bear, Gong Tang, Priya Rastogi, Charles E Geyer, Qing Liu, André Robidoux, James N Atkins, Luis Baez-Diaz, Adam M Brufsky, Rita S Mehta, Louis Fehrenbacher, James A Young, Francis M Senecal, Rakesh Gaur, Richard G Margolese, Paul T Adams, Howard M Gross, Joseph P Costantino, Soonmyung Paik, Sandra M Swain, Eleftherios P Mamounas, Norman Wolmark. The effect on overall and disease-free survival (OS & DFS) by adding bevacizumab and/or antimetabolites to standard neoadjuvant chemotherapy: NSABP Protocol B-40 [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 PD2-1.

Background: Initial fi ndings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor – positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical signifi cance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial fi ndings. Methods: Women (n = 13 388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confi dence intervals (CIs). Estimates of the net benefi t from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided. Results: After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically signifi cant. The net benefi t achieved with tamoxifen varied according to age, race, and level of breast cancer risk. Conclusions: Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all benefi cial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboem bolic events and endometrial cancer. Readily identifi able sub sets of individuals comprising 2.5 million women could derive a net benefi t from the drug. [J Natl Cancer Inst 2005;97:1652 – 62]

A B S T R AC T BACKGROUND Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)–negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response. METHODS

This report describes the light microscopic (LM), immunohistochemical (IHC), and electron microscopic (EM) features of a multifocal, nascent, and invasive myoepithelial carcinoma of the breast. By LM, the spindle cells disclosed fibrillar acidophilic cytoplasm, mild nuclear atypia, and a low mitotic index. Myoepithelial differentiation was established through IHC (single- and double-labeling techniques) and EM: periductal and infiltrating spindle cells coexpressed total muscle actin, a-smooth muscle actin, vimentin, cytokeratin 14, and pankeratin, and their EM features were characteristic of myoepithelial cells, i.e., perinuclear tonofilaments, subplasmalemmal bundles of microfilaments with dense bodies, intermediate junctions, poorly developed desmosomes, pinocytic vesicles, and fragmented external lamina. No invasive epithelial cells disclosed luminal differentiation (by LM, IHC, EM), identifying, thus, this neoplasm as a pure spindle cell myoepithelial carcinoma of the breast.

Bisphosphonates reduce the incidence of skeletal-related events (fractures, pain, hypercalcemia) in patients (pts) with bone metastases from breast cancer. By inhibiting osteoclast function and subsequent bone turnover they may inhibit the growth of bone (and other) metastases. Their role in preventing or delaying the development of bone (or other) metastases in pts with early breast cancer is uncertain. Three previous trials of oral clodronate have given mixed results. The largest trial (placebo-controlled) and a smaller open-label trial suggested that oral clodronate benefitted pts with improved bone metastases-free survival (BMFS) and overall survival (OS), but a third open-label study showed no benefit with an apparent detrimental effect on survival. Studies of IV zoledronate in open-label trials in early breast cancer have also shown mixed results: the AZURE trial in pts with node positive breast cancer showed no benefit in disease-free survival (DFS) or OS with a possible effect in pts aged over 60. The ABCSG-12 trial in GnRH (plus tamoxifen or anastrozole) treated women with early breast cancer showed a small DFS benefit for those receiving IV zoledronate but no BMFS or OS benefit. Methods: B-34 is a prospective, randomized, double-blind, phase III clinical trial in pts with stage 1, 2 or 3 breast cancer assessing oral clodronate 1600mg daily for 3 years compared to placebo given alone or in addition to adjuvant chemo- or hormone therapy. Stratification is by age ( Results: 3323 patients were accrued — 1662 in Group A and 1661 in Group B. As of March 31, 2011, 54 pts were declared ineligible: 23 in Group A and 31 in Group B. The average time on study is 101.3 months. Patient characteristics were evenly distributed throughout both groups. Approximately 75% of pts in each group had negative axillary lymph nodes and some 78% in each group were ER and/or PR positive. About 64% of pts were age 50 or over. Oral clodronate was generally tolerable, toxicities observed being mainly due to the concomitant systemic chemotherapy. One pt in Group A had a 1 mm area of osteonecrosis on the palatal taurus. Compliance, as expected with trials of oral medications, has been a problem. 1910 pts completed 3 years of therapy. Event rates were slower than anticipated. This final analysis assesses a total of 598 events in the two arms. Conclusions: This trial is the largest placebo-controlled study of an oral bisphosphonate in patients with early breast cancer and will provide further information on the role of bisphosphonates in breast cancer management. Supported for NSABP by NCI U10CA12027, −37377, 69651, 69974; and Bayer Schering Pharma Oy; for ECOG by U10CA021115; for NCCTG by U10CA25224; for SWOG by U10CA38926. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-3.

1058 Background: Eribulin (E) is a non-taxane, tubulin- and microtubule-targeting agent. In the randomized, phase III EMBRACE trial, disease-free survival and overall survival were prolonged in E v...

PURPOSE To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

PURPOSE To determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer. PATIENTS AND METHODS Women (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759 eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR was evaluated for a pathologic complete response (pCR). RESULTS Breast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy was proposed for 86% of women with tumors < or = 2 cm, 70% with tumors 2.1 to 5.0 cm, and 3% with tumors > or = 5.1 cm. Clinical tumor size and nodal status influenced the physician's decision. Overall, 12% more lumpectomies were performed in the preoperative group; in women with tumors > or = 5.1 cm, there was a 175% increase. CONCLUSION Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm, since women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy.

52 Background: Sentinel node biopsy (SNB) is used in breast cancer patients that present with clinically negative nodes. In this setting, most guidelines do not support the use of immunohistochemistry (IHC) and recommend against completion node dissection (CND) when only isolated tumor cells (pN0(i+)) or micrometasases (pN1mi) are identified. When SNB is used after neoadjuvant therapy (NAT), the relevance of ypN0(i+) and ypN1mi sentinel nodes (SNs) and the value of IHC are not well established. The goals of this study are to determine if CND should be recommended in the presence of ypN0(i+) or ypN1mi SNs and if IHC should be used to evaluate SNs after NAT. Methods: From March 2009 to December 2012, 152 women with biopsy proven node positive breast cancer were accrued to the multicentric prospective SN FNAC trial. After NAT, SNB was followed by a CND in all participants. SNs were cut in serial slices no thicker than 2 mm. Hematoxylin and eosin stains (H and E) were done on all slices, and if negative, IHC was used. The size of the largest SN metastasis and the primary method of identification (H and E or IHC) were recorded. ypN0(i+), ypN1mi and ypN1 SNs were considered as positive. Pathology was centrally reviewed. Results: 145 women were eligible for the trial. Axillary pathologic complete response rate = 34% (49/145). SNB success rate = 88% (127/145). False negative rate = 8.4% (7/83). If ypN0(i+) SNs are classified as node negative, the false negative rate is increased to 13.3% (11/83). For patients with ypN0(i+) (n=7), ypN1mi (n=8) and ypN1 (n=61) SNs, the rates of non-SN involvement are 57%, 38% and 56% respectively (p=NS). 40% (27/68) of positive SNBs are primarily detected by IHC. This is increased to 64% (9/14) for the identification of SN metastases ≤ 2mm. Conclusions: After NAT, particularly when presenting with biopsy proven node positive breast cancer, patients with ypN0(i+) and ypN1mi SNs have a significant rate of non-SN involvement. In the absence of evidence to show that a CND can be safely avoided, efforts should be made to identify even minimal amounts of disease when SNBs are done following NAT. IHC is useful to increase the detection of small SN metastases in this setting. Clinical trial information: NCT00909441.

574 Background: Biomarkers of bone turnover, including urine N-telopeptide (uNTx) and serum C-telopeptide (sCTx) reflect tumor-related bone breakdown and have been used as surrogate measures of response to therapy in trials. Vascular endothelial growth factor (VEGF) levels correlate with extent of bone metastases (BM). We assessed whether vandetanib, an inhibitor of VEGF, epidermal growth factor receptor and RET signalling, improved uNTx response when added to fulvestrant (F) in patients with BM. Methods: Postmenopausal patients with bone only, or bone predominant, hormone receptor positive MBC were randomised to F (500mg IM day 1, 14, 28, then monthly) with either vandetanib (100mg PO OD) (FV) or placebo (FP) until progression. The primary objective was uNTx response (>30% reduction from baseline). uNTx was collected at baseline, weekly to wk 4, at wk 12 and then every 12 wks. Secondary objectives included PFS, OS, RECIST response, pain and toxicity. Results: 61 patients were allocated to FV and 68 to FP. Median age was 59. 18% had received 1 prior chemotherapy regime and 73% prior endocrine therapy for MBC. uNTx response (n=124 pts) was 64% for FV vs. 52% for FP (p=0.20). No difference was detected between groups for median PFS; 6 months for FV vs. 4.8 months for FP, HR=0.93 (95% CI: 0.64 to 1.36). 16 patients died in FV arm vs. 21 in the FP arm, HR=0.71 (95% CI: 0.37 to 1.36). For those patients with measurable disease, clinical benefit rates were 41% and 43%, respectively, p=1.00. Serious adverse events were similar, 3.3% for FV vs. 5.9% for FP. Elevated baseline uNTx (>65 nM BCE/mmol Cr) was prognostic for PFS, HR=1.62 (95% CI: 1.08 to 2.43 and for mortality, HR= 2.4 (95% CI: 1.2 to 4.6). In an exploratory analysis uNTx was predictive of responsiveness to FV for PFS, HR=0.60 when uNTx >65 vs. HR=1.37 when uNTx

Background: Triple negative breast cancers (TNBCs) are an aggressive subtype of breast cancers, associated with a marked genomic instability, and an especially poor prognosis if they are or become resistant to chemotherapy. There is little data about the mechanisms of resistance to chemotherapy in TNBCs. Methods: The Q-CROC-3 study involves the collection of pre and post-chemotherapy biopsies from patients with TNBC in the neoadjuvant and metastatic settings. In parallel, we generated paclitaxel (PTX)-resistant TNBC cell lines. Molecular profiling including whole exome sequencing, array comparative genomic hybridization (CGH), microRNA and gene expression profiling is being performed on resistant and parental tumors and cell lines. The innovative approach in our analytic strategy is the genomic analysis of tumor subpopulations flow sorted by ploidy. This approach provides a deeper view of tumor heterogeneity and also enables the removal of contaminating stromal cells prior to genomics analysis. Results: We have developed standard operating procedures for tumor collection and processing adapted to downstream analyses. We emphasize pathological evaluation and measurement of tumor cellularity for each biopsy. Of the 41 patients recruited so far, pre-chemo and post- chemo specimens are available for 21 patients. Of these, 7 did not have enough tumor content in the biopsies collected and 9 pairs are available for analysis. Using flow-sorted array CGH, we could obtain aneuploid sub-fractions from snap frozen biopsies with as little as 17% tumor content. We observed relative increases in tumor sub-fractions after chemotherapy and identified novel copy number alterations (CNAs) in the post-chemotherapy tumors, not detectable by array CGH of the unsorted tumor sample. In parallel, we identified known molecular factors of resistance to PTX in TNBC cell lines, as well as novel mutations in DNA repair genes. Conclusion: Methods for biopsy collection and processing need to be adapted to downstream analyses. With flow sorting aCGH, it is possible to detect CNAs previously undetectable in unsorted specimens. These studies will identify molecular factors of chemotherapy resistance and novel therapeutic targets in TNBCs. Disclosure: All authors have declared no conflicts of interest.

BACKGROUND In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment. PURPOSE We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared. METHODS In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided. RESULTS Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. CONCLUSIONS AND IMPLICATIONS The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.

Introduction Patients with isolated local and regional recurrences (ILRR) of breast cancer (BC) have a high risk of developing distant metastasis and dying from BC. We investigated the impact of chemotherapy (C) on disease-free survival (DFS) and overall survival (OS) after ILRR. Methods Patients with resected ILRR were stratified according to prior chemotherapy (yes vs. no), ER and/or PgR status of the recurrent tumor (both negative vs. either positive), and location of recurrence (breast vs. scar/chest wall vs. lymph nodes). Radiation, hormone and HER2 directed therapies were delineated in the protocol. Participants were randomly assigned to receive C or none. Multidrug C for at least 4 courses was recommended. Drug selection was at the discretion of the investigator. Slow accrual led to premature closure of the trial before achieving the planned sample size of 265. Results The trial accrued 162 patients (C, 85; control, 77) from 2002–2010. The groups were balanced in regard to the characteristics listed in the table below. At a median follow up of 4.9 years, there were 24 (28%) DFS events and 9 (11%) deaths in the C group compared with 34 (44%) DFS events and 21 (27%) deaths in the control group, corresponding to a 5-year DFS of 69% vs. 57%, [DFS HR (C/control) = 0.59, 95% CI (0.35, 0.99)], p =0.046] and a 5-year OS of 88% vs. 76%, [OS HR (C/control) = 0.41, 95% CI (0.19, 0.89)], p =0.02]. The results remained significant for both DFS and OS in multivariable Cox proportional hazards modeling controlling for ILRR location, disease-free interval, ER status and prior adjuvant chemotherapy. Adjuvant C was particularly effective for women with ER-negative ILRR: 5-year DFS 67% vs. 35%, [DFS HR (C/control) = 0.32, 95% CI (0.14, 0.73)], p =0.007] and OS 79% vs. 69%, [OS HR (C/control) = 0.43, 95% CI (0.15, 1.24)], p =0.12]. Results for the ER-positive ILRR cohort were: 5-year DFS 70% vs. 69%, [DFS HR (C/control) = 0.94, 95% CI (0.47, 1.89)], p =0.87] and OS 94% vs. 80%, [OS HR (C/control) = 0.40, 95% CI (0.12, 1.28)], p =0.12]. Conclusion Adjuvant chemotherapy should be recommended for patients with completely resected isolated loco-regional recurrences of breast cancer, in particular, if the recurrence is not sensitive to endocrine therapy. Funding NCI PHS grants U10-CA-37377, -69974, -12027, -69651, CA-75362. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-2.

87 Background: Resistance to chemotherapy is the underlying cause of death in most patients dying of breast cancer. Patients with early stages of breast cancer whose tumor is or becomes resistant to chemotherapy have a poor prognosis, while women with advanced breast cancer live as long as their tumors respond to chemotherapy. Because of the great difficulty of obtaining clinical samples from drug resistant tumors in patients, there is scant information about molecular factors from actual drug resistant tumors. This project aims to systematically profile resistant triple negative breast cancers (TNBCs) in order to discover molecular “resistance” genes/proteins as a first step to develop strategies to overcome drug resistance. Methods: Paired biopsies are collected from TNBC patients (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Results: We have currently enrolled 28 patients in the neoadjuvant setting and 3 metastatic patients. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. In parallel, we have generated acquired resistance to paclitaxel in a panel of TNBC cell lines. These cell lines will also undergo genomic profiling and exome sequencing to identify molecular markers of resistance that will be correlated with the markers found in patient samples. Conclusions: This project will allow us to identify the molecular factors responsible for drug resistance in TNBCs and enable the elaboration of strategies to overcome resistance.

LBA506 Background: The purposes of this trial are to determine the effect of substituting lapatinib (L) for trastuzumab (T) in combination with weekly paclitaxel (WP) following AC as well as adding L to T with WP following AC on pathologic complete response (pCR) rates. Methods: Women with HER2-positive operable breast cancer received standard AC q3wks x 4 cycles followed by WP (80 mg/m2) on days 1, 8, and 15 q28 days x 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, patients received trastuzumab to complete 52 wks of HER2-targeted therapy. The primary endpoint is pCR breast. For each of the two primary comparisons, the Fisher’s exact test was used to test the equality of pCR rates. A Hochberg-type step-up procedure was applied to address multiple testings and to control the family-wise error rate at 0.05. Results: 51% were clinically node positive and 63% had HR+ tumors. pCR assessments were available from 519 of 529 patients. pCR percentage was 52.5% for AC→WP+T, 53.2% (p=0.9) for AC→WP+L, and 62% (p=0.075) for AC→WP+TL. pCR percentages in the HR+ subset were 46.7%, 48% (p=0.85), and 55.6% (p=0.18), respectively, and were 65.5%, 60.6% (p=0.57), and 73% (p=0.37) in the HR- cohort. The corresponding pCR breast and nodes percentages were 49.1%, 47.4% (p=0.74), and 60.4% (p=0.04). Grade 3/4 toxicities include diarrhea in 2%, 20%, 27% (p

1025 Background: Pazopanib is an oral, small molecule inhibitor of VEGFR-1, -2, and-3, PDGFR-α, and -β, and c-kit tyrosine kinases. The purpose of this trial was to determine the activity and safety profile of pazopanib when added to neoadjuvant WP following AC in LABC. The primary endpoint was pathologic complete response in the breast and nodes (pCR-BN). Methods: Women with HER2-negative stage IIIA-IIIC breast cancer were treated with AC (60 mg/m2/600 mg/m2) for 4 cycles every 3 weeks followed by WP 80 mg/m2 on days 1, 8, and 15 every 28 days for 4 cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Postoperatively, pazopanib was given for 6 months. The regimen would be considered active if ≥14 responses (16% pCR rate in breast and nodes) were observed in 87 evaluable patients. Patients were considered evaluable if they received at least 1 dose of pazopanib. Results: Between July 2009 and March 2011, 101 pts (median age 51 yrs, range 30-71) were enrolled; 56% had stage IIIA, 34% stage IIIB, and 10% stage IIIC disease. 74 pts (73%) had ER-and/or PR-positive tumors and 27 pts (27%) were triple negative. 8 patients did not begin pazopanib. The pCR-BN rate in evaluable patients for whom surgical information was known was 18% (16/89). The pCR-BN rate in ER positive disease was 9% (6/65) and was 42% (10/24) in TNBC. Toxicities observed with WP and pazopanib included diarrhea (gr 2/3, 10%/5%), hand-foot syndrome (gr 2/3, 11%/1%), hypertension (gr 2/3, 12%/3%), neuropathy (gr 2/3, 14%/1%), and neutropenia (gr 3/4, 25%/1%). Liver toxicity during WP and pazopanib included ALT (gr 2/3/4, 13%/7%/1%), AST (gr 2/3, 7%/7%), and total bilirubin (gr 2, 2%). Conclusions: A regimen of WP and pazopanib following AC was active as neoadjuvant therapy in women with LABC and met the pre-specified criteria of interest. The activity in TNBC was notable. The toxicity profile of WP and pazopanib was consistent with previous experience. Support: GlaxoSmithKline.

TPS1139 Background: Resistance to chemotherapy or targeted agents is the cause of death in most patients dying of breast cancer and one of the major challenges presently faced by oncologists. In triple negative breast cancers (TNBCs), drug resistance emerges quicker than in other breast cancer subtypes and contributes to the poor prognosis seen in these patients. The lack of targeted therapies to treat TNBC highlights the important need to better understand the molecular mechanisms contributing to chemotherapy resistance in order to develop new therapeutic strategies. However, the difficulty in obtaining tissue samples from drug resistant tumors has been one of the limiting factors in this field of study. Methods: We have designed a prospective phase II clinical trial where paired biopsies are collected from chemotherapy resistant TNBCs (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Metastatic sites eligible for biopsy include liver, lung, skin and lymph nodes. This study is presently recruiting at 5 major health centers in Quebec and will soon open in the USA. We have currently enrolled 13 patients in the neoadjuvant setting and 2 metastatic patients. Major challenges in patient enrolment will be discussed. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Collection of clinical data will allow molecular profiling data to be linked to clinical response data so as to determine DNA, RNA and protein factors correlated with tumor resistance to chemotherapy.

616 Background: With the introduction of targeted therapy based on tumor subtypes, an increasing number of patients that receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR). Previous studies have shown that the accuracy of MRI is poor at predicting the response to neoadjuvant chemotherapy in locally advanced and often non-resectable breast cancers, where the rate of pCR is low. The purpose of this study is to evaluate MRI’s ability to predict a pCR in operable breast cancers after neoadjuvant therapy. Methods: All patients enrolled in the NSABP B-40, B-41, FB-5 and FB-6 protocols in a single tertiary care centre, that had an MRI done before and after neoadjuvant therapy were reviewed. A radiologist, blinded to the pathology results, interpreted the pre- and post- treatment MRI’s and made a prediction as to whether or not patients would have a pCR. In this study, a true negative was defined as a reading of a complete response on MRI that was confirmed as a pCR on final pathology. pCR was defined as having no residual invasive or in situ disease in the breast. Results: 129 women with a median age of 51 years were identified. 90% had invasive ductal carcinoma; 8% had invasive lobular. 58% were ER+, 21% were triple negative and 21% were Her2+. 16% of patients had a pCR. 25% of patients had no residual invasive cancer in the breast. pCR rates for ER+ tumors was 5%, triple negative 37%, and Her2+ 26%. 19% of patients that had a pCR had a total mastectomy. The sensitivity and specificity of MRI for predicting residual disease were 88% and 52% respectively. The positive predictive value was 90% and the negative predictive value was 46% with an accuracy of 82%. Conclusions: MRI has limited value for determining which patients had a pCR after neoadjuvant chemotherapy, even in operable breast cancers. When residual disease is suspected on MRI, it is unlikely that a pCR has been achieved. Surgical excision following neoadjuvant therapy remains the gold standard to identify which patients have achieved a pCR. Other modalities will need to be used in order to accurately determine which patients would be eligible for studies evaluating non operative management following neoadjuvant therapy.

LBA1000 Background: The primary aims were to determine whether adjuvant DD AC→PG will be superior to DD AC→P as well as to TAC in DFS and to compare the relative DFS of TAC and DD AC→P. Secondary endpoints include survival and toxicity. Methods: From Nov 3, 2004 to May 3, 2007, 4894 women were randomized; 1630 to TAC (docetaxel [T] 75 mg/m2, doxorubicin [A] 50 mg/m2, cyclophosphamide [C] 500 mg/m2 q3 wks x 6), 1634 to DD AC→P (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 followed by P 175 mg/m2 q2 wks x 4), and 1630 to DD AC→PG (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 → P 175 mg/m2 + G 2000 mg/m2q2 wks x 4). Primary G-CSF support was required and erythropoiesis-stimulating agents (ESA) were used at investigator discretion. 52% were postmenopausal, 65% had 1 - 3 positive nodes, and 80% had HR+ breast cancer. Log-rank tests were used for pair-wise comparisons of the primary (DFS) and secondary (OS) endpoints among the three treatment arms. Results: With 64 months median follow-up, 5-year DFS in DD AC→PG group was 80...

LBA1005 Background: The addition of capecitabine (X), gemcitabine (G), and bevacizumab (B) to taxanes have each improved PFS in metastatic breast cancer. The primary aims of this trial were to determine if adding X or G to docetaxel (T) → AC will increase breast pathologic complete response (pCR) rates in operable, HER2-negative breast cancer and if adding B to T-based regimens →AC will increase pCR rates. Secondary aims included assessment of clinical complete response (cCR) rates. Methods: Pts received one of 3 T-based regimens, with or without B, 15mg/kg, q3wks x 4: T 100 mg/m2 day 1; T 75 mg/m2 day 1 and X 825 mg/m2 BID days 1-14; or T 75 mg/m2 day 1 and G 1000 mg/m2 days 1 and 8. Pts then received preoperative AC x 4, with or without B for the initial 2 cycles of AC. Pts randomized to B resumed B for 10 postop doses. The primary endpoint was pCR in the breast. The maximum of the standardized pairwise differences between pCR rate for the T → AC regimen and for the other 2 T-based regimens was used as the test statistic to adjust for multiple comparisons. Fisher’s exact test was used to compare the arms with and without B. Results: The groups were balanced, with 47% clinically node+, 56% poorly differentiated, and 59% HR+. Assessments for pCR were available from 1180 of 1206 randomized patients. pCR for TX and TG were 29.7% and 32% vs. 32.7% for T. Neither TX nor TG increased cCR rates relative to T (58.3% and 60.4% vs. 61.5%). TX and TG increased toxicity. Addition of B increased the pCR rate (28.4 vs. 34.5%, p=0.027) and the cCR rate (55.8 vs. 64.3%, p=0.007). The effect of B was predominantly in the HR+ subset (15.2 vs. 23.3%, p=0.008) with minimal effect in the HR- subset (47.3% vs. 51.3%, p=0.44). Grades 2/3/4 toxicities increased with B were HTN (1/

9005 Background: Survivorship care plans (SCPs) are recommended for patients who have completed primary treatment and are transitioning to routine follow-up care. SCPs are considered to have face v...

Background: In an ethnically-homogeneous population, it is valuable to identify founder mutations in cancer-predisposing genes. Founder mutations have been found in four breast cancer predisposing genes in French-Canadian breast cancer families. The frequencies of the mutant alleles have not been measured in a large series of unselected breast cancer patients from Quebec, nor in healthy controls. These estimates are necessary to measure their contribution to the hereditary burden of breast cancer in Quebec and to help develop genetic screening policies which are appropriate for the province.Methods: We studied 564 French-Canadian women with early-onset invasive breast cancer who were treated at a single Montreal hospital. Patients had been diagnosed at age 50 or less, and were ascertained between 2004 and 2008. We screened all 564 patients for nine founder mutations; four in BRCA1, three in BRCA2 and one each in PALB2 and CHEK2. We also studied 6433 DNA samples from newborn infants from the Quebec City area to estimate the frequency of the nine variant alleles in the French-Canadian population.Results: We identified a mutation in 36 of the 564 breast cancer cases (6.4%) and in 35 of 6443 controls (0.5%). In the breast cancer patients, the majority of mutations were in BRCA2 (54%). However, in the general population (newborn infants), the majority of mutations were in CHEK2 (54%). The odds ratio for breast cancer to age 50, given a BRCA1 mutation was 10.1 (95% CI: 3.7 to 28) and given a BRCA2 mutation was 29.5 (95% CI: 12.9 – 67). The odds ratio for breast cancer to age 50, given a CHEK2 mutation was 3.6 (95% CI: 1.4 – 9.1). One-half of the women with a mutation had a first or second-degree relative diagnosed with breast or ovarian cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 902.

Background: Joint symptoms have been commonly reported by patients using aromatase inhibitors (AIs). A survey of women who received AI therapy reported 47% of AI-joint related problems (Crew, JCO 2007;25:3877-83.) The exact etiology has not been identified. The purpose of this pilot prospective study was to determine the nature, the onset, and the incidence of AI musculosketelal syndromes (AIMS trial) as well as to correlate with ultrasound imaging, serum biochemistries and pain/depression assessment.Methods: Between 05/08 and 11/08, 30 women with hormone responsive invasive breast cancer initiated treatment with anastrazole 1mg daily during or following radiation therapy. Patients could have received postoperative chemotherapy but no prior hormonal therapy. Patients evaluations were performed at 48 hours after the initiation of treatment and at 1 week(w), 3w, 5w, 7w, 12w and 24w. Clinical examination by a rheumatologist, ultrasound imaging and serum biochemistries were performed at the same visit (C-Reactive Protein, Rheumatoid Factor, Antinuclear Antibody, Vitamin D, Estradiol (LC/LC/LC). Questionnaires were used to assess pain and depression (Brief Pain Inventory; Beck Depression Inventory).Results: After rheumatological examination, all 30 patients presented musculosqueletal conditions at baseline. Twenty out of 30 patients (66%) pain symptoms did not increase during AI administration. Five patients (16%) reported pain symptoms of moderate intensity at baseline, which were not exacerbated during AI administration. Only five other patients (16%) had an increase in pain symptoms that could be possibly related to AIs; four patients presented exacerbation of pain symptoms due to pre-existing osteoarthritic conditions and two patients developed new pain symptoms due a tenosynovial phenomenon (one patient presents these two patterns). No correlation was seen with any of the above serum biomarkers. All patients with pain symptoms were treated with NSAIDs and their pain symptoms rarely reached severe intensity. All patients were compliant as shown by estradiol levels measured by LC/LC/LC and none of the patients had to interrupt their treatment with anastrazole. Differences in gene expression in blood mononuclear cells isolated from patients from different groups are being investigated using microarray profiling.Conclusion: This study suggests that only 16% of the patients had and exacerbation of their pain symptoms or developed new pain symptoms in the upper limbs that could be possibly related to AI administration. The study also suggests that 1) it is important to evaluate the patient's pain prior to starting a treatment with AIs to avoid misinterpretation of pain causes and 2) pain symptoms should be treated in order to avoid their escalation which could lead to the unnecessary interruption of vital anticancer therapy. A larger prospective trial is underway. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4090.

584 Background: Bevacizumab with chemotherapy improves outcomes in patients with metastatic breast cancer. The purpose of this trial was to determine the activity and safety profile of bevacizumab with chemotherapy in women with LABC. Methods: Between November 2006 and August 2007, 45 women with HER-2 negative LABC initiated preoperative standard AC x 4 followed by docetaxel 75 mg/m2 IV and capecitabine 825 mg/m2 BID days 1–14 (TX) every 21 days for 4 cycles. Bevacizumab 15 mg/kg IV was given concurrently with chemotherapy every 21 days for a total of 6 preoperative doses. Postoperatively, bevacizumab was resumed for a total of 10 doses. Primary endpoint was pathologic complete response rate (pCR) in the breast. The secondary endpoints include clinical response rates and toxicity. Results: The median age was 50 yrs (range 30–78). 30 patients had stage IIIA (67%), 12 stage IIIB (27%), and 3 stage IIIC (7%) disease. Of these, 10 (22%) had inflammatory breast cancer. 27 patients (60%) had ER-positive disease. A pCR in the breast was documented in 4/44 (9%) patients, which included negative axillary nodes. A complete clinical response was noted in 14/45 (31%). One patient did not have surgery due to progression. Toxicities included hand-foot (grade 2/3–33%/22%), mucositis (grade 2/3–49%/27%), and febrile neutropenia (grade 3–24%). Conclusions: This regimen demonstrated only modest activity with substantial toxicity, and does not appear to warrant further evaluation. This clinical trial is being conducted through the support of Genentech and Roche. [Table: see text]

Abstract #6084 We conducted a nested case-control study of 280 French-Canadian women with breast cancer who were non-gene carriers (BRCA) and 280 women without cancer who were also non-gene carriers. A validated lifestyle questionnaire and a food frequency questionnaire were administered to obtain relevant information. It was found that age at the time the subjects reached maximum body mass index (BMI) was significantly associated with breast cancer risk [OR=2.83; 95% CI: (2.34-2.81)]. In addition, a significant association was noted between maximum weight gain at age 20 years [OR=1.68; 95% CI: (1.10-2.58)], 30 years [OR=1.96; 95% CI: (1.46-3.06)], and 40 years [OR=2.50; 95% CI: (1.72-3.97)] and breast cancer risk. Women who smoked more than 9 pack-years of cigarettes had a higher risk of breast cancer [OR=1.59; 95% CI: (1.57-2.87)]. Subjects who engaged in moderate physical activity had a 52% decreased risk of breast cancer [OR=0.48; 95% CI: (0.31-0.74)], but this was not evident for vigorous physical activity. It was observed that total energy intake was significantly associated with breast cancer risk [OR=2.54; 95% CI: (1.67-3.84)]. Women who drank more than 8 cups of coffee per day had 40% more chance of developing breast cancer [OR=1.40 (95% CI: (1.09-2.24)]. Subjects who consumed more than 9 grams of alcohol (ethanol) per day had the highest risk of breast cancer [OR=1.55 (95% CI: (1.02-2.37)]. None of the other nutrients and dietary components was significantly associated with non-gene carrier breast cancer risk. This study suggests that BMI, maximum weight gain during the second, third and fourth decades, smoking, total energy intake, and high intake of both alcohol and coffee may increase the risk of breast cancer among non-gene carrier French-Canadian women, while moderate physical activities may reduce the risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6084.

9000 Background: Wage losses after breast cancer may result in considerable financial burden. More women now participate in the workforce and breast cancer is managed using multiple treatment modalities that could lead to long work absences. We evaluated the burden from wage losses and determinants among Canadian women in the first 12 months after newly diagnosed non-metastatic breast cancer. Methods: This prospective cohort study was conducted among 800 women from 8 hospitals (participation 83%) of whom 459 were working at diagnosis. For these latter women, information on potential determinants of wage losses, work absences, compensation received and perception of financial situation was collected by 3 telephone interviews over the year. Information on medical characteristics came from medical files. The main outcome was the relative loss, namely wages lost divided by annual wages the woman would have earned had she not been absent from work. ANOVA was used to identify determinants. Results: The median relative loss in the first year after diagnosis for the 403 women reporting an absence or reduced work hours was 19% or $5,502 (Can dollars). Multivariate analysis showed that the mean relative loss was 13% for women who reported that breast cancer was not at all costly compared to 22%, 33% and 38% among women who said that breast cancer was a bit, quite or very costly, respectively (ptrend No significant financial relationships to disclose.

Information is presented from 555 patients with Dukes B and C rectal cancers treated by curative resection who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-01 between November 1977 and October 1986. Their average time on study was 64.1 months. The patients were randomized to receive no further treatment (184 patients), postoperative adjuvant chemotherapy with 5-fluorouracil, semustine, and vincristine (MOF) (187 patients), or postoperative radiation therapy (184 patients). The chemotherapy group, when compared with the group treated by surgery alone, demonstrated an overall improvement in disease-free survival (P = .006) and in survival (P = .05). Employing the proportional hazards model, a global test was used to determine the presence of treatment interactions. Investigation of stratification variables employed in this study indicated that sex, and to a lesser extent age and Dukes stage, made individual contributions to the disease-free survival and the survival benefit from chemotherapy. When evaluated according to sex, the benefit for chemotherapy at 5 years, both in disease-free survival (29% vs. 47%; P less than .001; relative odds, 2.00) and in survival (37% vs. 60%; P = .001; relative odds, 1.93), was restricted to males. When males were tested for age trend with the use of a logistic regression analysis, chemotherapy was found to be more advantageous in younger patients. When the group receiving post-operative radiation (4,600-4,700 rad in 26-27 fractions; 5,100-5,300 rad maximum at the perineum) was compared to the group treated only by surgery, there was an overall reduction in local-regional recurrence from 25% to 16% (P = .06). No significant benefit in overall disease-free survival (P = .4) or survival (P = .7) from the use of radiation has been demonstrated. The global test for interaction to identify heterogeneity of response to radiation within subsets of patients was not significant. In conclusion, this investigation has demonstrated a benefit from adjuvant chemotherapy (MOF) for the management of rectal cancer. The observed advantage was restricted to males. Postoperative radiation therapy reduced the incidence of local-regional recurrence, but it failed to affect overall disease-free survival and survival.

Chemotherapy and chemoimmunotherapy of Stage IV B malignant melanoma were compared in 88 patients. Chemotherapy consisted of DTIC 250 mg/M2 of the body surface area daily x five days and actinomycin-D 2 mg/M2 on day 1 repeated every 3--4 weeks. Chemoimmunotherapy consisted of the same regimen plus C. parvum 2 mg/M2 I.V. daily for 14 days before every third cycle of chemotherapy, plus 2 mg/M2 I.V. daily on days 7 and 14 of each 21--28 day chemotherapy cycle. There was 32 evaluable chemotherapy and 33 evaluable chemoimmunotherapy patients and the groups were well balanced for clinical and pathologic as well as prognostic variables. The complete and partial remission rates, remission and survival durations, and hematologic and gastrointestinal toxicities were different in the two randomized groups being 6 and 3%, 9 and 9%, 7.6 and 12 months, 8.8 and 6.0 months, 20 and 16%, and 62 and 70%, respectively for these parameters. This difference was not statistically significant. Therefore, it can be concluded that the results of chemotherapy with actinomycin-D plus DTIC were not substantially different from those reported using DTIC alone, and that we cannot recommend the addition of actinomycin-D to DTIC for palliative management in these patients. Furthermore, C. parvum immunotherapy did not add to chemotherapy in terms of remission rate, remission duration, or survival for patients with Stage IV B malignant melanoma.

OBJECTIVE To determine whether in the previous National Surgical Adjuvant Breast and Bowel Project (NSABP) studies of node-negative breast cancer there were either cohorts of patients with a prognosis favorable enough to preclude using systemic therapy or subsets of patients who failed to benefit from the treatments. DESIGN Randomized clinical trials with stratification after surgery. SETTING NSABP trials at institutions in the United States and Canada. PATIENTS Data were collected on 731 eligible patients (Protocol B-13) with estrogen-receptor-negative tumors who randomly received either no therapy after surgery or sequential methotrexate and fluorouracil (M----F) followed by leucovorin. Data were also collected on 2834 patients (Protocol B-14) with estrogen-receptor-positive tumors who randomly received either placebo or tamoxifen treatment. The percentage of patients surviving disease-free was determined through 4 years of follow-up using life-table estimates. INTERVENTIONS Protocol B-13 patients received 12 courses of M----F given intravenously on days 1 and 8 every 4 weeks. Leucovorin therapy was begun 24 hours after M----F administration. Protocol B-14 patients received 5-year treatment with either tamoxifen (10 mg twice daily by mouth) or placebo. RESULTS When the outcome of untreated patients in either trial was related to the stratification variables, women were found to have a disease-free survival of less than 80% through 4 years of follow-up. This percentage is apt to decrease because the probability of treatment failure increases with time. In both trials, all subsets of women benefited from M----F or tamoxifen therapy. CONCLUSIONS The disease-free survival of all cohorts of node-negative patients with estrogen-receptor-negative or estrogen-receptor-positive tumors was poor enough to justify systemic treatment. The benefits of the therapies used are insufficient to eliminate the need for assessing putatively better regimens.