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Supplementary Figure 1 a. Doxorubicin resistance of DOXO-R C8 cells was further validated using the cell viability assay (SRB) following 48 hrs treatment with DOXO, n=4 independent experiment, 3 replicates/experiment. **p0.6 and pval

Table S18: Two-way ANOVA

Perspectives on this Article from Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer

Table S1: List of regions of genes with increased CNV (>= 0.5) and gene expression (>= 0.5) in DOXO-R cells compared to parental cells Table S2: List of all fold change and pvalue of DOXO-R C1 and C8 (vs parental cells) from gene expression analysis. Table S3. GSEA using the C5 module for the 1852 genes with gene expression fold change > 1.5 (pval < 0.05) in DOXO-R C1 and C8 Table S4. GSEA using the C5 module for the 407 genes with gene expression fold change > 1.5 (pval < 0.05) and CNV change > 0.5 Table S5: Mean LOG2FC of genes commonly up-regulated in C1 and C8 Table S6: Proteins that are significantly upregulated according to the following criteria. (i) only present in one or two of the Dox resistant cell lines (**) with at least 3 and 2 unique peptides, respectively. (ii) At least 1.5-fold upregulated in both cell lines with a maximum relative standard deviation (RSD) of 31% across control replicates and 25% RSD across resistant cell line replicates. Table S7: GSEA using the C5 module for the 98 overexpressed proteins in DOXO-R vs parental cells Table S8: mRNA fold change (POST vs PRE NAC) for 9 chemoresistant TNBC patients. Table S9: GSEA using the C5 module for NEO2 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S10: GSEA using the C5 module for NEO24 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S11: GSEA using the C5 module for NEO25 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S12: GSEA using the C5 module for NEO27 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S13: GSEA using the C5 module for NEO28 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S14: GSEA using the C5 module for NEO30 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S15: GSEA using the C5 module for NEO31 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S16: GSEA using the C5 module for NEO35 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis. Table S17: GSEA using the C5 module for NEO44 up regulated genes > 2.5 FC. The complete list of genes are listed below the GSEA analysis.

The major obstacle in successfully treating triple-negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous preclinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphologic phenotype, which consists of polyploid giant cancer cells giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC-resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy. These findings thus reveal a novel mechanism of chemotherapy resistance that has therapeutic implications in the treatment of drug-resistant cancer.Implications:These findings underlie the importance of a novel morphologic–metabolic phenotype associated with chemotherapy resistance in TNBC, and bring to light novel therapeutic targets resulting from vulnerabilities in this phenotype, including the expression of PLIN4 essential for stabilizing lipid droplets in resistant cells.

Purpose:In NSABP B-41, pathologic complete response (pCR) was associated with prolonged survival among women with HER2-positive operable breast cancer treated with neoadjuvant chemotherapy and lapatinib, trastuzumab, or the combination. We used a large human breast cancer gene expression panel to select candidate prognostic biomarkers for pCR among women treated with trastuzumab in NSABP B-41.Patients and Methods:Eligible patients had a baseline preadjuvant treatment core biopsy sample, known pCR status, and no withdrawal of consent. We analyzed extracted RNA using the human nCounter Breast Cancer 360 gene expression panel. Gene counts were normalized to housekeeping genes and transformed into logarithmic scale with base 2. To screen for candidate genes and metagene signatures prognostic of pCR, we used univariate logistic regression. Variable selection was done by multivariable logistic regression with lasso regularization.Results:Analyses of data from 130 patients revealed that a composite of gene expression from 19 genes and one gene signature appeared to predict pCR in women with HER2-positive early-stage breast cancer undergoing neoadjuvant chemotherapy with trastuzumab-containing regimens. The identified genes are involved in important pathways such as epithelial–mesenchymal transition, adhesion and migration, estrogen receptor signaling, DNA damage and repair, apoptosis, and proliferation. The AUC from a 10-fold cross-validation on predicting pCR, with these 20 genomic markers in a logistic regression model, was 0.73.Conclusions:The expression level of ERBB2, ESR1, and a few other genomic markers was highly predictive of pCR after trastuzumab-containing regimens. These findings need to be validated and calibrated in future studies.

Tables S1-S6 and Figures S1-S5

PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHODS: NSABP B-36 was a phase III clinical trial originally designed as a 2x2 factorial study comparing 6 cycles of FEC-100 (5-FU, epirubicin, cyclophosphamide) to 4 cycles of conventional AC (Adriamycin/cyclophosphamide) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS).RESULTS: Between May 2004-July 2008, 2,722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR=1.09; 95% CI 0.92-1.29, p-value=0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR=1.32, 95% CI=1.05-1.66) compared to receptor-negative patients (HR=0.86, 95% CI=0.66-1.11) (treatment-by-receptor status interaction p-value=0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR=1.06; 95% CI 0.84-1.35, p-value=0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group.CONCLUSIONS: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100.ClinicalTrials.gov: NCT00087178

Background: Locoregional lymph node involvement has historically been used as the most important deciding factor for the administration of chemotherapy in the adjuvant setting of breast cancer patients. The 21-gene Breast Recurrence Score® assay (the assay) is emerging as an important tool to assist with chemotherapy decisions amongst hormone receptor (HR)-positive, node-positive breast cancer (BC) patients. Previous studies have suggested that node-positive patients with low Recurrence Score (RS) results do not benefit from chemotherapy. We wanted to better understand the impact of the assay upon physician treatment decisions and treatment cost in this patient cohort. Methods: We conducted a multicenter prospective observational trial for ER/PR-positive HER2-negative BC patients that have undergone surgical treatment for T1-T3 disease and 1-3 positive lymph nodes. Physicians were required to complete a questionnaire indicating treatment choice prior to and post availability of Recurrence Score results. Patients were enrolled in the study from the time of consent to 6 months after the start of adjuvant therapy. The primary endpoint was change in the physician’s recommendation for chemotherapy prior to and post assay results. Secondary endpoints include the change in recommendation for additional growth factor (GF) supportive therapy, change in physician’s expressed level of confidence, and changes in estimated cost of recommended treatments prior to and post assay results. Results: 70 patients were enrolled between March 2018 and September 2019 at five hospital centers, as part of the McPeak Sirois Group of Quebec. The median age of the cohort was 61 years (range, 38 to 82 years). 18.5% (n=13) of the cohort consisted of patients < 50 years, and 81.4% (n=57) were > or = to 50 years. 64.3% (n=45) of the patients had one positive lymph node and 35.7% (n=25) of the patients had 2 or 3 positive lymph nodes. 25.7% (n=18) of the patients had a RS < 11 and 68.6% (n=48) had a RS result between 11-25. For the entire cohort, we found that the proportion of patients for whom chemo-hormonal therapy was recommended was reduced by an absolute 67.1% by knowledge of the RS result (OR (odds of having chemo-hormonal therapy post-RS recommendation versus pre-RS recommendation) = 0.03 [95% CI: 0.01-0.08]; P or = to 50 years. Changes in treatment recommendation were identified for patients with one positive node, 73.3% (OR=0.02 [95% CI: 0.01-0.07]; P Conclusions: Overall, we found that the 21-gene Breast Recurrence Score® assay changed physician treatment decisions in about two-thirds of all patients with hormone receptor-positive, node-positive BC, regardless of the number of positive nodes (up to 3). The assay increased physician confidence and was associated with an important decrease in treatment cost. Taken together, the assay is a cost-effective approach that can decrease the use of chemotherapy amongst HR-positive, node-positive BC patients in Quebec. Citation Format: Saima Hassan, Rami Younan, Erica Patocskai, Louise Provencher, Brigitte Poirier, Lucas Sideris, Pierre Dubé, Jean-Francois Boileau, Catalin Mihalcioiu, André Robidoux. A prospective multicenter study evaluating the impact of the 21-Gene Breast Recurrence Score® upon physician treatment decision and cost in lymph node-positive breast cancer patients in Quebec [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-27.

Background: Although the role of the 21-gene Breast Recurrence Score® assay is well established to predict response to adjuvant chemotherapy in the setting of node-negative hormone receptor (HR)-positive, HER2-negative breast cancers (BC), fewer studies have evaluated the assay in the neoadjuvant setting. Due to the correlation between a high Recurrence Score® (RS) result and pathological complete response (pCR), the Breast Recurrence Score assay has been used to aid in selecting between chemotherapy (CT) or endocrine therapy. We wanted to further understand the impact of the assay upon physician treatment recommendations and the use of chemotherapy in this patient cohort. Methods: We conducted a multicenter, prospective, observational study in patients with clinically node-negative HR-positive, HER2-negative BC with T2-T3 disease being considered for neoadjuvant therapy. Physicians were required to complete two questionnaires indicating treatment choice, including CT, endocrine therapy, or surgery, prior to and post availability of RS result. Patients were followed up for 6 months after commencement of neoadjuvant therapy. The primary objective was to evaluate the change in the physician’s recommendation for neoadjuvant CT prior to and post assay results. As a secondary objective, we also evaluated the impact of the RS result on physician’s expressed level of confidence. Results: A total of 70 patients were enrolled between April 2018 and November 2021 at five hospital centers, as part of the McPeak Sirois Group of Quebec. The median age of the cohort was 60 years (range, 30 to 79 years). 24.3 % (n=17) of the cohort consisted of patients aged < 50 years, and 75.7% (n=53) were ≥ to 50 years. 29.0% (n=20) of the patients had a RS < 16, 39.1% (n=27) had a RS between 16-25, and 31.9% (n=22) had a RS > 25. For the entire cohort, the RS result led to a net reduction in chemotherapy recommendation by 33.3% (OR (odds of having CT post-RS recommendation versus pre-RS recommendation) = 0.23 [95% CI: 0.12-0.44]; P< 0.0001), and 39.2% net reduction in the use of chemotherapy at 6-month follow-up (OR = 0.18 [95% CI: 0.09-0.35]; P< 0.0001). Furthermore, the RS result led to a 35.3% net reduction in physician recommendation of CT for patients < 50 years (OR = 0.19 [95% CI: 0.04-0.83]; P=0.027) and a 32.7% net reduction for patients ≥ 50 years (OR = 0.24 [95% CI: 0.11-0.50]; P=0.0001). For patients with a RS < 16, there was a reduction in CT recommendation by 75.0%, and by 44.4% for patients with a RS between 16 - 25 (OR = 0.15 [95% CI: 0.06-0.38]; P< 0.0001). Moreover, RS results led to an increase in confidence in physician treatment decisions for 59.4% of patients (OR = 12.53 [95% CI: 5.46-28.78]; P< 0.0001). Conclusion: We determined that the 21-gene Breast Recurrence Score assay altered neoadjuvant treatment decisions, leading to a reduction in the use of chemotherapy by about one-third, regardless of age. Additionally, the assay increased physician confidence in their treatment recommendation for about 60% of patients. This demonstrates the potential clinical utility of the assay to decrease the use of CT in the neoadjuvant setting amongst HR-positive, node-negative BC patients in Quebec. Citation Format: Mariya Yordanova, Lucas Sideris, Pierre Dubé, Jean-Francois Boileau, Julie Lemieux, Catalin Mihalcioiu, Sylvie Levesque, Marie-Claude Guertin, Erica Patocskai, Rami Younan, André Robidoux, Saima Hassan. The impact of the 21-gene Recurrence Score® assay upon physician treatment recommendations in the neoadjuvant setting in lymph node-negative breast cancer patients in a multicenter prospective study in Quebec [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-39.

BackgroundThe NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted.Patients and methodsPatients completed the QOL questionnaire at baseline, during treatment, and every 6months through 36months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF.ResultsFEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6months (P

Obesity has been associated with poor breast cancer (BC) outcomes. We investigated whether a standardized, telephone-based weight loss lifestyle intervention in the adjuvant setting would impact BC outcomes. We conducted a multicenter trial randomizing women 1:1 to mail-based educational material alone (control) or combined with a standardized, telephone-based lifestyle intervention that focused on diet, physical activity, and behavior and involved 19 calls over 2 years to achieve up to 10% weight loss. In all, 338 (of 2150 planned) T1-3, N0-3, M0 hormone receptor positive BC patients with body mass index (BMI) ≥24 kg/m2 receiving adjuvant letrozole were randomized (enrolment ended due to funding loss). The primary outcome was disease-free survival (DFS); secondary outcome was Overall Survival (OS). At 8 years’ median follow-up, in a planned analysis, DFS and OS were compared using the Kaplan–Meier method. Baseline BMI and other characteristics were similar between study arms. In all, 22 of 171 (12.9%) in the lifestyle intervention arm versus 30 of 167 (18.0%) in the education had DFS events; the hazard ratio (HR) was 0.71 (95% confidence interval [CI]: 0.41–1.24, p = 0.23). Although loss of funding reduced sample size, we view these hypothesis generating results as compatible with our hypothesis of a potential beneficial effect of a lifestyle intervention on DFS. They provide support for completion of ongoing randomized controlled trials of the effect of lifestyle interventions in BC outcomes.

Background The 21-gene Breast Recurrence Score (RS) assay, “the assay”, has led to a paradigm shift for patients with hormone receptor-positive, node-negative early breast cancer and is emerging as an important tool to assist physician-patient decisions in foregoing chemotherapy in node-positive patients. We wanted to better understand the impact of the RS assay in node-positive patients upon physician treatment decisions and treatment cost in Quebec, Canada. Patients and Methods We conducted a multicenter, prospective observational trial for Estrogen/Progesterone Receptor (ER/PR)- positive, Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer patients with 1-3 positive lymph nodes. Physicians completed a questionnaire indicating treatment choice prior to and post availability of RS results. The primary endpoint was change in the physician’s recommendation for chemotherapy prior to and post assay results. Secondary endpoints included change in physician’s expressed level of confidence, and changes in estimated cost of recommended treatments prior to and post assay results. Results For the entire cohort, physician recommendation for chemotherapy was reduced by an absolute 67.1% by knowledge of the RS assay result (P < .0001). Physician recommendation of chemotherapy was decreased by 75.9% for patients RS result Conclusion Altogether, we established that the assay led to a two-third reduction in the use of chemotherapy, and was a cost-effective approach for hormone receptor-positive, node-positive breast cancer.

Background Presentation to multidisciplinary cancer conferences (MCCs) supports optimal treatment of young women with breast cancer (YWBC). However, research shows barriers to MCC practice, and variation in professional attendance and referral patterns. A checklist may help overcome these barriers and support MCC practice with YWBC. Methods We developed, piloted and evaluated an MCC checklist in sites participating in a pan-Canadian study (RUBY; Reducing the bUrden of Breast cancer in Young women). A survey assessed checklist processes and impacts, and checklist data were analysed for checklist uptake, MCC presentation rates and MCC processes including staff attendance. Results Fifteen RUBY sites used the checklist (~50%), mostly for data collection/tracking. Some positive effects on clinical practice such as increased presentation of YWBC at MCC were reported, but most survey participants indicated that MCC processes were sufficient without the checklist. Conversely, checklist data show that only 31% of patients were presented at MCC. Of those, 41% were recommended treatment change. Conclusion Despite limited checklist uptake, there was evidence of its clinical practice benefit. Furthermore, it supported data collection/quality monitoring. Critically, checklist data showed gaps in MCC practice and low MCC presentation rates for YWBC. This contrasts with overall provider perceptions that MCCs are working well. Findings suggest that supports for MCC are needed but may best take the form of clear national practice recommendations and audit and feedback cycles to inform awareness of good MCC practice and outcomes. In this setting, tools like the MCC checklist may become helpful in supporting MCC practice.

Background The Adjuvant Zoledronic Acid (ZA) study in early breast cancer (AZURE) showed correlation between a non-amplified MAF gene in the primary tumor and benefit from adjuvant zoledronic acid (ZA). Adverse ZA outcomes occurred in MAF-amplified patients. NSABP B-34 is a validation study. Methods A retrospective analysis of MAF gene status in NSABP B-34 was performed. Eligible patients were randomly assigned to standard adjuvant systemic treatment plus 3-years oral clodronate (1600mg/daily) or placebo. Tumors were tested for MAF gene amplification, and analyzed for their relationship to clodronate for disease-free survival (DFS) and overall survival (OS) in MAF non-amplified patients. All statistical tests were 2-sided. Results . MAF status was assessed in 2,533 available primary tumor samples from 3,311 patients. Of these, 37 withdrew consent; in 77 samples no tumor was found; 536 assays did not meet quality standards, leaving 1,883 (77.8%) evaluable for MAF assay by fluorescence in situ hybridization (947 from placebo, and 936 from clodronate arms). At 5 years, in MAF non-amplified patients receiving clodronate, DFS improved by 30% (hazard ratio =0.70, 95% confidence interval = 0.51-0.94, P=0.02). OS improved at 5 years (hazard ratio =0.59, 95% confidence interval = 0.37–0.93, P=0.02) remaining statistically significant for clodronate throughout study follow-up. Conversely, adjuvant clodronate in women with MAF-amplified tumors was not associated with benefit, but possible harm in some subgroups. Association between MAF status and menopausal status was not seen. Conclusions Non-amplified MAF showed statistically significant benefits (DFS and OS) with oral clodronate, supporting validation of the AZURE study.

Purpose NSABP B-41, a phase three randomized trial, evaluated neoadjuvant lapatinib, trastuzumab, or the combination with chemotherapy in patients with HER2-positive operable breast cancer. Though no significant difference in pathologic complete response (pCR) was found among the three arms, pCR was associated with prolonged survival. We analyzed tumor intrinsic subtypes with Prediction Analysis of Microarray 50 in a subset of B-41 patients to determine their value in predicting HER2-targeting benefit. Methods Pearson’s Chi square test and logistic regression were used to compare pCR in the breast and nodes (ypT0/Tis ypN0). Kaplan–Meier estimates and Cox models were used to compare event-free and overall survival among subtypes. Results Intrinsic subtypes were determined in 271 baseline core biopsy samples. The pCR rate among patients with HER2-enriched (HER2E) subtype was greater compared to other subtypes combined (120/197, 60.9% versus 19/74, 25.7%; p

Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. To evaluate the predictive and prognostic values of circulating tumor DNA (ctDNA) in this setting, we analyzed tumor and serial bloods from 26 TNBC patients collected prior, during, and after NAC. Individual digital droplet PCR assays were developed for 121 variants (average 5/patient) identified from tumor sequencing, enabling ctDNA detection in 96% of patients at baseline. Mutant allele frequency at baseline was associated with clinical characteristics. Levels drastically fell after one cycle of NAC, especially in patients whose tumors would go on to have a pathological complete response (pCR), but then rose significantly before surgery in patients with significant residual tumor at surgery (p = 0.0001). The detection of ctDNA early during treatment and also late at the end of NAC before surgery was strongly predictive of residual tumor at surgery, but its absence was less predictive of pCR, especially when only TP53 variants are considered. ctDNA detection at the end of neoadjuvant chemotherapy indicated significantly worse relapse-free survival (HR = 0.29 (95% CI 0.08–0.98), p = 0.046), and overall survival (HR = 0.27 95% CI 0.075–0.96), p = 0.043). Hence, individualized multi-variant ctDNA testing during and after NAC prior to surgery has prognostic and predictive value in early TNBC patients.

The primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2+) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses. pCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes. The numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34–66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24–54]) or neratinib (33% [95%CI 20–50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR−) tumors had a higher pCR rate than HR+ tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR. Combining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR− patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2+ patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting. ClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.

PURPOSE Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer. PATIENTS AND METHODS A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. RESULTS At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx. CONCLUSION The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2–overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.

Targeted axillary dissection (TAD) with a radioactive seed is a new and promising technique to evaluate the axillary status in post-neoadjuvant chemotherapy (NACT) node-positive breast cancer patients. This study aims to evaluate the feasibility of TAD with a radioactive seed in a Canadian setting. We conducted a retrospective observational study of a prospectively gathered database of patients having undergone TAD with a radioactive seed implanted in a proven metastatic axillary node, between 2015 and 2017 in our institution. An iodine-125 radioactive seed was implanted under ultrasound guidance by trained radiologists. Patients then underwent standard sentinel lymph node biopsy (SLNB) using technicium-99 and blue dye, as well as selective removal of the node containing the radioactive seed. Data was gathered from electronic medical records and chart review. Nine patients with a median age of 54 underwent TAD for unilateral breast cancer post-NACT between 2015 and 2017, three of which were "triple-negative". A median of 3 lymph nodes were removed, including that which contained the radioactive seed. Postoperative pathological evaluation showed 4 patients with positive nodes and 5 pathologic complete responses in the axilla. In all patients, the seed had been accurately positioned in a positive node (no false negatives). The seed also located a positive retropectoral node that would otherwise have been missed using standard dual tracer SLNB. No complications due to the use of the radioactive seed were encountered. All implanted seeds were identified and retrieved within the pathology specimen. In our experience, TAD with a radioactive seed combined to dual tracer SLNB is an accurate and safe method of evaluating the axillary lymph node status in post-NACT node positive breast cancer patients. Further studies with larger cohorts are warranted to ensure continued feasibility and reproducibility of our positive results. Citation Format: Boulva K, Rodriguez-Qizilbash S, Guilarte L, Lazizi S, Robidoux A, Younan R, Patocskai E. Radioactive seed and targeted axillary dissection: A feasibility study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-21.

Neoadjuvant systemic therapy (NST) can facilitate breast conserving surgery (BCS) for large cancers. While hormone receptor positive (HR+) cancers respond to neoadjuvant chemotherapy (NCT), pathologic complete responses (pCR) are unlikely. Neoadjuvant hormonal therapy (NHT) may make BCS possible with less toxicity than NCT. We hypothesized that the Oncotype Dx® 21-gene Recurrence Score (RS), could guide the decision to treat with NHT versus NCT to facilitate BCS. This hypothesis is based on the ability of the RS to identify ER+ patients (pts) likely to benefit from adjuvant CT vs unlikely to benefit, as well as prior studies showing that pts with a low RS have no pCRs when receiving NCT (Yardley, et al 2015). Methods: This prospective multi-center study enrolled pts with HR+, HER2-negative, invasive breast cancers not suitable for BCS (size ≥ 2 cm). Diagnosis was made by core needle biopsy (bx). Tissue blocks from the bx's were sent to Genomic Health for RS testing. Pts whose tumors had a RS < 11 were to receive NHT; pts with RS >25 tumors were to receive NCT; pts with midrange RS of 11-25 were randomized to NHT or NCT. The primary objective was the feasibility of randomizing pts with RS values 11-25 between NHT and NCT. The primary endpoint was whether 1/3 or more of randomized pts would refuse assigned treatment. Secondary endpoints included: clinical partial and complete response (cPR, cCR) rates, overall clinical response rates (CR), pCR in the breast, pCR in the breast and nodes and successful BCS. One-sample binomial test was used to compare the observed refusal rate with 1/3, along with its 95% CI. Fisher's exact test, logistic regression (for a binary endpoint), and/or ordinal regression (for an ordinal endpoint) were used to compare the 4 treatment groups for secondary endpoints. Results: Seven US and Canadian centers enrolled 64 pts; 5 were excluded (1 delay in RS result, 1 lost block, 1 HR testing discrepancy, 2 not eligible). Of 33 pts with RS 11-25, 5 (15%; 95% CI =2.9% - 27.4%) refused assignment to NCT (2 chose NHT and finished the study). This was significantly lower than the 33% target (binomial test, p=0.0292). Results for other endpoints are shown in the Table (according to treatment received); the total number of pts for the analyses is 55; 1 pt had missing data for clinical response. Results According to TreatmentTreatment GroupRS25 NCTOverall PNN=12N=18N=11N=14 cCR8.3%22.2%36.4%28.6%0.0422cPR75%27.8%36.4%64.3% CR (cCR + cPR)83.3%50%72.7%92.9%0.0490pCR Breast8.3%6%021.4%NSpCR Breast + Nodes00014.3%NSSuccessful BCS75%72.2%63.6%57.1%NS Conclusions:This pilot showed the feasibility of using the RS to guide NST, with only a 15% refusal rate of randomly assigned treatment. Of greater interest is the finding that pts with a RS 25 treated with NCT had the highest CR (cCR + pCR) and pCR rates. These results demonstrate that conducting a similarly designed larger trial is feasible and suggests that for pts with a low RS, NHT is a potentially effective strategy. Citation Format: Bear HD, Wan W, Robidoux A, Rubin P, Limentani S, White, Jr. RL, Granfortuna J, Hopkins JO, Oldham D, Rodriguez A, Sing AP. Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: A multi-center trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-10-04.

Fear of high local recurrence rate associated with immediate breast reconstruction (IBR) following total mastectomy for breast cancer might be a contributing factor to the low rate of immediate reconstruction performed in Quebec. The aim of this study was to demonstrate the oncological safety of total mastectomy with immediate breast reconstruction. A retrospective chart review of all patients who underwent total mastectomy with immediate breast reconstruction at the University of Montreal Hospital Center between 2006 and 2015 was performed. 375 patients (420 cases) met the inclusion criteria. The mean age was 51.5 years (25-77). The median follow-up was 45.6 months (0.4-115.2). Clinical cancer staging was done according to the American Joint Committee on Cancer (AJCC) criteria. 349 cases (83.1%) were classified as Stage < cIIb and 71 cases (16.9%) as ≥ cIIb. 73 patients (19.5%) received neoadjuvant chemotherapy, 113 (30.1%) received adjuvant chemotherapy and 91 (21.7%) received postoperative radiotherapy. Only 4 patients (3.5%) had a significant delay in receiving adjuvant chemotherapy and 4 patients (4.4%) had a delay in initiation of radiotherapy. In total, there were 12 (2.6%) local recurrences and 29 (7.7%) distant recurrences. The results of this study demonstrate a low rate of local recurrence that is comparable to the current litterature. Total mastectomy in association with immediate breast reconstruction is therefore an oncologically safe approach for the treatment of breast cancer and should be more widely adopted by medical centers throughout Quebec. Citation Format: Younan RJ, Al Khaldi M, Maalouf C, Guez M, Boulva K, robidoux A, Nassif E, Poljicak M, BouMerhi J, Bernier C, Patocskai E. Total mastectomy and immediate breast reconstruction for breast cancer: A ten-year Canadian single institution experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-14-13.

Background: The achievement of pCR (breast and axilla) is strongly prognostic for event-free (EFS) and overall survival (OS) in EBC (Cortazar 2014), and modulation of therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR (Von Minckwitz 2019). We sought to investigate prognostic factors for EFS and OS among patients with and without pCR following neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. Methods: We used individual data from 3,710 patients randomized in 11 neoadjuvant trials for HER2-positive EBC with N≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone-receptor (HR)-positive vs. HR-negative disease, and for patients who achieved pCR (pCR+; ypT0/is, ypN0) vs. patients who did not achieve pCR (pCR-). Results: The median follow-up overall was 61.2 months. The table shows hazard ratios and 5-year Kaplan-Meier estimates of OS (5yr OS) according to HR and pCR. Comparable results were observed for EFS. Both cT (1-2 vs. 3-4) and cN (cN- vs. cN+) were independent prognostic factors for OS in most subsets, including in pCR+ patients. Conclusions: These results confirm that patients achieving pCR have far better long-term outcomes than patients who do not, and that traditional poor prognostic features namely tumour size and nodal status remain important even after a pCR, with no clear evidence that the relative impact of unfavourable (cT3-4 or cN+) features is different in patients who achieve a pCR than in those who did not. Key words: neo-adjuvant therapy, HER2-targeted therapy, pathological complete response, prognostic factors, overall survival Funding: German Breast Group HR pCRBaseline cT/cN DeathsPatients5yr OS (%)Hazard ratio* [95% CI]HR+ pCR+cT1-2/cN-521298.6%1.0 (reference)(N= 637)cT3-4/cN-46592.9%0.49 [0.21-1.14]cT1-2/cN+720095.1%0.82 [0.34-1.99]cT3-4/cN+1016094.0%0.40 [0.13-1.25]HR+ pCR-cT1-2/cN-1737796.3%1.0 (reference)(N=1399)cT3-4/cN-2514381.8%0.51 [0.36-0.73]cT1-2/cN+4844888.9%0.71 [0.49-1.03]cT3-4/cN+6443184.9%0.36 [0.23-0.58]HR- pCR+cT1-2/cN-319698.1%1.0 (reference)(N=860)cT3-4/cN-89090.4%0.56 [0.32-0.98]cT1-2/cN+1928092.4%0.49 [0.24-0.98]cT3-4/cN+3029489.5%0.27 [0.12-0.64]HR- pCR-cT1-2/cN-2114083.2%1.0 (reference)(N=814)cT3-4/cN-207871.4%0.46 [0.34-0.64]cT1-2/cN+4225181.6%0.76 [0.53-1.09]cT3-4/cN+11634561.9%0.35 [0.22-0.56]*Hazard ratio cT1-2/cN- vs. higher risk cohorts Citation Format: Sibylle Loibl, Michael Untch, Marc Buyse, André Robidoux, Luca Gianni, Andreas Schneeweiss, Pierfranco Conte, Martine Piccart, Hervé Bonnefoi, Christian Jackisch, Valentina Nekljudova, Joseph Costantino, Pinuccia Valagussa, Colin Neate, Richard Gelber, Coralie Poncet, Pierre Squifflet, Everardo Saad, Dominik Heinzmann, Carsten Denkert, Charles E Geyer, Javier Cortes, Valentina Guarneri, Evandro de Azambuja, David Cameron, Gustavo Ismael, Gunter von Minckwitz, Norman Wolmark, Patricia Cortazar. Pathologic complete response (pCR) and prognosis following neoadjuvant chemotherapy plus anti-HER2 therapy of HER2-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-02.

BackgroundNRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical complications after surgery in patients who did or did not receive bev.MethodsA total of 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15mg/kg every 3weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24months following study entry.ResultsEarly surgical complications were significantly more frequent in the bev group (25.4 vs. 18.9%; trend test p = 0.008), but most were grade 1-2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4 vs. 3.1%; trend test p = 0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8 vs. 5.1%; trend test p = 0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (

Background The aim of this study was to evaluate the wage losses incurred by spouses of women with nonmetastatic breast cancer in the 6 months after the diagnosis. Methods A prospective cohort study of spouses of women diagnosed with nonmetastatic breast cancer who were recruited in 8 hospitals in the province of Quebec (Canada) was performed. Information for estimating wage losses was collected by telephone interviews conducted 1 and 6 months after the diagnosis. Log-binomial regressions were used to identify personal, medical, and employment characteristics associated with experiencing wage losses, and generalized linear models were used to identify characteristics associated with the proportion of usual wages lost. Results Overall, 829 women (86% participation) and 406 spouses (75% participation) consented to participate. Among the 279 employed spouses, 78.5% experienced work absences because of breast cancer. Spouses were compensated for 66.3% of their salary on average during their absence. The median wage loss was $0 (mean, $1820) (2003 Canadian dollars). Spouses were more likely to experience losses if they were self-employed or lived 50 km or farther from the hospital. Among spouses who experienced wage losses, those who were self-employed or whose partners had invasive breast cancer lost a higher proportion of wages. Conclusions Although spouses took some time off work, for many, the resulting wage losses were modest because of compensation received. Still, the types of compensation used may hide other forms of burden for families facing breast cancer.

The sentinel node biopsy following neoadjuvant chemotherapy (SN FNAC) study has shown that in node-positive (N+) breast cancer, sentinel node biopsy (SNB) can be performed following neoadjuvant chemotherapy (NAC), with a low false negative rate (FNR = 8.4%). A secondary endpoint of the SN FNAC study was to determine whether axillary ultrasound (AxUS) could predict axillary pathological complete response (ypN0) and increase the accuracy of SNB. The SN FNAC trial is a study of patients with biopsy-proven N+ breast cancer who underwent SNB followed by completion node dissection. All patients had AxUS following NAC and the axillary nodes were classified as either positive (AxUS+) or negative (AxUS−). AxUS was compared with the final axillary pathology results. There was no statistical difference in the baseline characteristics of patients with AxUS+ versus those with AxUS−. Overall, 82.5% (47/57) of AxUS+ patients had residual positive lymph nodes (ypN+) at surgery and 53.8% (42/78) of AxUS− patients had ypN+. Post NAC AxUS sensitivity was 52.8%, specificity 78.3%, and negative predictive value 46.2%. AxUS FNR was 47.2%, versus 8.4% for SNB. If post-NAC AxUS− was used to select patients for SNB, FNR would decrease from 8.4 to 2.7%. However, using post-NAC AxUS in addition to SNB as an indication for ALND would have led to unnecessary ALND in 7.8% of all patients. AxUS is not appropriate as a standalone staging procedure, and SNB itself is sufficient to assess the axilla post NAC in patients who present with N+ breast cancer.

The major obstacle in successfully treating triple-negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous preclinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphologic phenotype, which consists of polyploid giant cancer cells giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC-resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy. These findings thus reveal a novel mechanism of chemotherapy resistance that has therapeutic implications in the treatment of drug-resistant cancer. Implications: These findings underlie the importance of a novel morphologic–metabolic phenotype associated with chemotherapy resistance in TNBC, and bring to light novel therapeutic targets resulting from vulnerabilities in this phenotype, including the expression of PLIN4 essential for stabilizing lipid droplets in resistant cells.

PURPOSECDK4/6 inhibitors are used to treat estrogen receptor (ER)–positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy.PATIENTS AND METHODSPostmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase.RESULTSThree hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (−4.1 v −2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of −97.4% versus −88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (−0.80 v −0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia.CONCLUSIONAdding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.

In remote dynamic elastography, the amplitude of the generated displacement field is directly related to the amplitude of the radiation force. Therefore, displacement improvement for better tissue characterization requires the optimization of the radiation force amplitude by increasing the push duration and/or the excitation amplitude applied on the transducer. The main problem of these approaches is that the Food and Drug Administration (FDA) thresholds for medical applications and transducer limitations may be easily exceeded. In the present study, the effect of the frequency used for the generation of the radiation force on the amplitude of the displacement field was investigated. We found that amplitudes of displacements generated by adapted radiation force sequences were greater than those generated by standard nonadapted ones (i.e., single push acoustic radiation force impulse and supersonic shear imaging). Gains in magnitude were between 20 to 158% for in vitro measurements on agar-gelatin phantoms, and 170 to 336% for ex vivo measurements on a human breast sample, depending on focus depths and attenuations of tested samples. The signal-to-noise ratio was also improved more than 4-fold with adapted sequences. We conclude that frequency adaptation is a complementary technique that is efficient for the optimization of displacement amplitudes. This technique can be used safely to optimize the deposited local acoustic energy without increasing the risk of damaging tissues and transducer elements.

Locally advanced breast cancer (LABC) is a good setting in which to monitor response to neoadjuvant chemotherapy, to downsize the tumor (which facilitates breast-conserving surgery), and to test newer agents in untreated patients. Eribulin (E) has shown activity in patients who have undergone previous taxane, anthracycline, and capecitabine treatment. We aimed to evaluate the neoadjuvant use of E followed by doxorubicin and cyclophosphamide (AC) in patients with HER2-negative LABC, using as a control a randomized group of women who received weekly paclitaxel (WP). Fifty women with LABC were accrued January-August 2013. Patients were randomized (1:2) to receive either WP (N = 19) for 12 treatments or E (N = 31) every 3 weeks for 4 cycles followed by AC every 3 weeks for 4 cycles before surgery. 17/19 patients who took WP and 25/30 who took E completed all cycles. Patients were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. Surgical pCR in breast and lymph nodes was determined by a local pathologist following chemotherapy. Forty-nine patients received ≥1 dose of neoadjuvant chemotherapy and are included in this analysis. Forty-eight underwent surgery; one had disease that was inoperable (on E) and is included as no-pCR patient. 17/19 of these patients who took WP completed 12 doses; 28/30 on E completed 4 cycles. Six discontinued treatment on WP, E, or AC. Both treatments were well tolerated. pCR on WP = 5/19(26 %) and on E = 5/30(17 %). Both regimens were equally well tolerated with no unexpected toxicities. pCR did not suggest higher activity with E than with other standard regimens in these LABC patients.

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 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.

Purpose An increasing proportion of patients (> 30%) with node-positive breast cancer will obtain an axillary pathologic complete response after neoadjuvant chemotherapy (NAC). If sentinel node (SN) biopsy (SNB) is accurate in this setting, completion node dissection (CND) morbidity could be avoided. Patients and Methods In the prospective multicentric SN FNAC study, patients with biopsy-proven node-positive breast cancer (T0-3, N1-2) underwent both SNB and CND. Immunohistochemistry (IHC) use was mandatory, and SN metastases of any size, including isolated tumor cells (ypN0[i+], ≤ 0.2 mm), were considered positive. The optimal SNB identification rate (IR) ≥ 90% and false-negative rate (FNR) ≤ 10% were predetermined. Results From March 2009 to December 2012, 153 patients were accrued to the study. The SNB IR was 87.6% (127 of 145; 95% CI, 82.2% to 93.0%), and the FNR was 8.4% (seven of 83; 95% CI, 2.4% to 14.4%). If SN ypN0(i+)s had been considered negative, the FNR would have increased to 13.3% (11 of 83; 95% CI, 6.0% to 20.6%). There was no correlation between size of SN metastases and rate of positive non-SNs. Using this method, 30.3% of patients could potentially avoid CND. Conclusion In biopsy-proven node-positive breast cancer after NAC, a low SNB FNR (8.4%) can be achieved with mandatory use of IHC. SN metastases of any size should be considered positive. The SNB IR was 87.6%, and in the presence of a technical failure, axillary node dissection should be performed. We recommend that SN evaluation with IHC be further evaluated before being included in future guidelines on the use of SNB after NAC in this setting.

One of the major challenges in biomarker development is the collection of tumor tissue of adequate quality for analysis. A prospective clinical trial was initiated to collect tissues from triple negative breast cancers prior to and after neoadjuvant chemotherapy in order to study the mechanisms of chemoresistance. Sixty patients had pre-chemotherapy biopsies performed by either a surgeon or a radiologist, while those with residual tumor after chemotherapy had research-only biopsies and/or surgical samples collected in liquid nitrogen, RNA-later and formalin. We examined each core for tumor cellularity, stromal content, and necrosis after which, RNA and DNA extraction was performed. We found that biopsies collected with ultrasound guidance were more likely to contain tumor than those collected by the surgeon. Patient reluctance to undergo research-only biopsies after chemotherapy was not a problem. Pre-chemotherapy tumor biopsies frequently did not contain any tumor cells (15%) or did not have ≥50% tumor content (63%). Indeed, 50% of patients had at least 2 pre-chemotherapy core biopsies with

Adjuvant systemic treatments reduce the risk of breast cancer recurrence following the local treatment of primary stage I-III breast cancers. For patients with hormone-positive breast cancers receiving hormonal therapy, the risk of distant recurrence is under 20% and therefore, many patients may potentially be spared of chemotherapy. Consequently, several molecular signatures based on gene expression were developed to better determine which breast cancer patients would benefit from chemotherapy. We present the case of a 62-year-old woman diagnosed with an early stage hormone receptor-positive breast cancer that was treated with a partial mastectomy. Oncotype DX (Genomic Health, Redwood City, CA) molecular testing was performed on the surgical specimen, which reported a recurrence score of 0. The patient commenced adjuvant radiotherapy during which she developed symptoms suggestive of bone metastasis and was subsequently diagnosed with a spinal cord compression that required neurosurgery and radiotherapy. Pathology review of the specimen from the spine surgery revealed a metastatic breast carcinoma with neuroendocrine differentiation. Molecular assays such as Oncotype DX are increasingly used to prognosticate patient outcomes and help determine who may avoid chemotherapy. This case report seeks to illustrate that such assays should not be used in the presence of rare histological subtypes like neuroendocrine breast cancers, which are often under-reported. The current status of personalized medicine and gene assays in breast cancer is reviewed and potential strategies are suggested to identify these rare cases to better orient diagnostic and treatment decisions.

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.

The study objectives were to identify key information components that would be the basic content of a brief informational intervention, developed from a population perspective, to empower individual couple members facing breast cancer and to validate the relevance and acceptability of these components.A review of information relevant to couples facing cancer presented in internet sites and documents of national cancer organizations was made to identify information components to include in a brief informational intervention. These information components were framed as messages, that is, very brief sentences or tips. To validate the relevance and acceptability of these messages, six focus groups were conducted in Quebec City and Montreal among women who had had breast cancer and their spouses. Reactions to the messages were synthesized by analyzing the verbatim transcripts.A total of 70 individuals (35 women with an average of 14 months since diagnosis and 35 spouses) participated in the groups. The content of almost all messages was seen as relevant, although nuances and improvements were discussed. However, the message format provoked irritation and will need improvement.Findings provide validation of the relevance, from the viewpoint of women and their spouses, of the message content to be part of a brief informational intervention intended to empower couples as they cope with breast cancer.Couples approved of the idea of being guided in their adjustment to breast cancer. However, the message format requires adaptation and further testing.

Background: Adjuvant trastuzumab (H) reduces cancer recurrence and improves survival in patients (pts) with HER2-amplified or overexpressing (IHC 3+ staining intensity) IBC. Two of the landmark trials that demonstrated the efficacy of H-based eligibility on HER2 testing performed at local site laboratories were found to contain a cohort of pts without amplification or IHC overexpression on tissue submitted for central testing. These HER2-low cohorts appeared to benefit from the addition of H, and efforts at external HER2 testing validation and laboratory explorations did not negate these findings. NSABP B-47 was performed to determine if these findings would be confirmed in a large prospective randomized trial. The primary aim was to determine whether the addition of H to chemotherapy (CT) regimens of AC→WP or TC (choice per investigator discretion) would improve invasive disease-free survival (IDFS). Methods: From 2/8/2011 to 2/10/2015, 3270 women were enrolled with 1630 pts randomly assigned to Arm 1 [TC: docetaxel 75mg/m2, cyclophosphamide 600 mg/m2 every 3 weeks x 6 cycles; or AC→WP: doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 or 3 weeks x 4 cycles followed by paclitaxel 80 mg/m2 every week x 12], and 1640 pts to Arm 2 [same CT regimens + 12 months of H]. Pts were stratified by IHC score (1+ vs 2+), number of positive nodes (0-3, 4-9, ≥10), hormone receptor status (ER or PgR positive vs both negative), and CT (TC vs AC→WP). Overall 58.5% were ≥50 years, 57% had tumors with IHC 1+, 17.3% were ER- and PgR-, 19.9% were node negative, and 27.4% had ≥4 positive nodes. TC was the intended CT regimen for 44.2%. Results: As of 7/31/2017, the median follow-up time was 46.1 months. We observed 264 IDFS events, which triggered the definitive analysis for the primary endpoint. The addition of H to CT showed a 5-year IDFS of 89.6% compared to 89.2% for CT alone (HR 0.98; 95%CI 0.77-1.26; P=0.90). The findings did not differ by level of HER2 IHC expression, level of lymph node involvement, or hormone receptor status. 5-year point estimates for RFI were 92.0% for CT+H compared to 92.2% for CT alone (HR 0.995; 95%CI 0.75-1.32; P=0.97). 5-year estimates for DRFI were 92.7% for CT+H and 93.5% for CT alone (HR 1.10; 95%CI 0.81-1.49; P=0.55). The addition of H did not change OS significantly with 5-year point estimates of 94.8% in CT+H vs 96.2% in CT alone (HR 1.33; 95%CI 0.91-1.94; P=0.14). 4.3% of women in the CT arm experienced Grade 4 or 5 toxicities compared to 5.0% in CT+H. Conclusion: The addition of H to CT did not demonstrate a reduction in IDFS, RFI, or DRFI in women with non-overexpressing but IHC measurable HER2 IBC. This prospective study did not confirm the retrospective findings in NSABP B-31 or N9831. The threshold of HER2 expression or genetic amplification for H benefit remains unchanged. Support: NCI U10-180868, -180822, -44066, UG1-189867, and Genentech, Inc. Citation Format: Fehrenbacher L, Cecchini RS, Geyer CE, Rastogi P, Costantino JP, Atkins JN, Polikoff J, Boileau J-F, Provencher L, Stokoe C, Moore TD, Robidoux A, Borges V, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low IBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-02.

594 Background: TNBC, the most aggressive form of breast cancer, is treated primarily with chemotherapy, even before surgery (neoadjuvant chemotherapy or NAC). The prognosis and need for adjuvant therapy depends greatly on the tumor response assessed by pathology (pCR). Highly sensitive and specific ctDNA assays have been shown to be of prognostic value in the metastatic settingbut not yet in earlier settings. Methods: Tissue was collected from 26 Q-CROC-03 clinical trial TNBC patients before, during and after NAC, prior to surgery. Whole exome sequencing on tumor tissues was used to select single nucleotide variants with high allele frequency (VAF), prioritizing TP53, to generateindividual digital droplet PCR (ddPCR) assays. An average of 5 variants (range 1-12) per patient were tested, for a total of 121 variants. A detection threshold was defined for each variant from a pool of normal controls. Median follow-up was 55 months. Results: ctDNA was detectable in 96% of patients at baseline, but 20% of the 121 variants were not detectable at any time point. At baseline, the mean VAF of all analyzed variants, but not of TP53 variants alone, was significantly correlated (p < 0.05) with tumor factors (tumor size, stage, grade, nodal status before and at surgery, RCB score) but not with patient age or BRCA1/2 mutation status. 87 variants (74%) were detected at baseline and their VAF fell by 86% after 1 cycle of chemotherapy (T1). The detection of ctDNA at T1 was associated with DFS (p = 0.027) while the detection of ctDNA at the last post-chemotherapy pre-surgery time point (T4) was strongly associated with pathological complete response (pCR) and both DFS (p = 0.013) and OS(p = 0.006). At this time point, 5 of 41 variants (12%) were detected in pCR patients vs 42 of 80 (53%) in non-pCR, while only 6 of the 15 (40%) non-pCR patients had detectable TP53 variants. Interestingly, for variants detected at baseline, the positive predictive value of T4 ctDNA for disease recurrence was 69%, similar to that of non-pCR, while the negative predictive value of no ctDNA at T4 was 89% for disease recurrence vs 80% for pCR. Conclusions: ctDNA detection after NAC prior to surgery is strongly predictive of disease-free survival and overall survival and is comparable to pCR as a prognostic factor in our cohort (NCT01276899).

511 Background: NSABP B-41 randomly assigned 529 patients (pts) with HER2 positive breast cancer to neoadjuvant trastuzumab (T), lapatinib (L), or combination (T+L), with weekly paclitaxel following doxorubicin and cyclophosphamide. No significant differences in pCR were found, but overall survival was significantly increased for pCR. Methods: RNA was extracted from FFPE tumor specimens, run on the NanoString Breast Cancer 360 Plus panel. Gene counts were normalized to include housekeeping genes, 33 biological signatures from 776 genes across 23 pathways and transformed into logarithm scale with base two. Univariate logistic regression was used to screen candidate genes and signatures that are prognostic of pCR, with false discovery rate controlled at 0.1. Multivariable logistic regression with lasso regularization was used for model selection. Results: 194 core biopsy samples were available; 69 treated with T, 64 with L and 61 with T+L. 20 prognostic genes are selected for trastuzumab-based regimens (TBR), including the epithelial-mesenchymal transition (HEMK1, GRB7, ERBB2, TMPRSS4), adhesion and migration (ITGB6, COL27A1, NRCAM), JAK-STAT (SOCS2), Hedgehog (LRP2), ER signaling (ELOVL2, MAPT), DNA damage and repair (NPEPPS, PRKDC), MAPK (DUSP6, PRKCB), Apoptosis (BCL2), proliferation (TFDP1). ERBB2 expression are associated with pCR in patients on TBR (OR = 1.73), but not for patients on L (interaction p = 0.01). HER2-Enriched correlation (p < 0.001), ESR1 (OR = 0.78, 95% CI = 0.69-0.88, p < 0.001), PD1 (OR = 1.68, 95% CI = 1.12-2.52, p = 0.01) and Tumor Inflammation Score (OR = 1.58, 95% CI = 1.18-2.11, p = 0.002) are associated with pCR in TBR. No genes or signatures were found to be predictive of treatment benefit from L added to T. Conclusions: BC360 highlighted tumor progression and signaling genes prognostic for TBR. HER2-Enriched correlation, ERBB2 and PD1 expression, and immune activation signatures were associated with pCR in TBR and may provide personalized treatment guidance.

Background: Obesity has been associated with poor BC outcomes. We investigated whether a standardized, telephone-based weight loss lifestyle intervention in recently diagnosed BC patients would lower recurrence and death rates. Methods: We conducted a multicenter RCT comparing mail-based educational material alone (control arm) or combined with a standardized, telephone-based lifestyle intervention (19 calls over 2 years, (intervention arm) that focused on diet (500-100 kcal/day deficit), physical activity (150-200 minutes of moderate-intensity activity per week) and behavior (compliance, relapse prevention) to achieve up to 10% weight loss. 338 (of 2150 planned) T1-3, N0-3, M0 ER/PgR+ BC patients with body mass index (BMI) ≥ 24 kg/m2 receiving adjuvant letrozole were randomized Aug 2007 to Jan 2010 (enrolment ended due to funding loss). Primary outcome was DFS; secondary outcome OS. Weight loss (5.3 vs 0.7% at 6 months and 3.6 vs 0.4% at 24 months in the intervention vs control arms, respectively) has been reported (JCO 2014;32:2331). At 8 years median follow-up (May 2018), DFS and OS were compared using Cox proportional hazards regression. Results: Mean age was 61.6 vs 60.4 years, mean BMI 31.4 vs 31.0 kg/m2 and adjuvant chemotherapy was received by 56.1 vs 57.5% in intervention vs controls arms respectively. T1/T2/T3 66.7/27.5/5.9% vs 61.7/33.5/3.6% and N0/1/2+ 62.6/28.7/8.8 vs 63.5/32.3/4.2% in intervention vs controls arms respectively. HER2+ in 8.8 vs 15.0% (intervention vs control). 20 of 171 (11.7%) in the lifestyle intervention arm vs 30 of 167 (18.0%) in the mail-based arm had DFS events, HR 0.71, 95%CI 0.41-1.24, p=0.23). DFS curves separated at 2 yrs; beyond 3-3.5 yrs separation approximated 5%. In a landmark DFS analysis of women alive at 24 months, DFS HR=0.68 (0.34-1.37, p=0.28). Conclusions: We identified fewer DFS events in the lifestyle intervention arm. Although loss of funding reduced sample size and lowered power, these results are consistent with a potential beneficial effect of a lifestyle intervention on DFS in postmenopausal ER/PgR+ BC patients. They provide strong support for completion of ongoing RCTs (e.g. BWEL) that will provide definitive evidence regarding the effect of lifestyle based weight loss on BC outcomes. Funded by Novartis Pharmaceuticals Inc.; Sponsored by the Ontario Clinical Oncology Group Citation Format: Goodwin PJ, Segal R, Vallis M, Ligibel JA, Pond GR, Robidoux A, Findlay BP, Gralow JR, Mukherjee SD, Levine MN, Pritchard KI. Lifestyle intervention study (LISA) in early breast cancer (BC): An RCT of the effects of a telephone-based weight loss intervention (with educational materials) vs educational materials alone on disease-free survival (DFS) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-04.

We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients.For this open-label, randomised phase 3 trial we recruited women aged 18 years or older with an ECOG performance status of 0 or 1 with operable HER2-positive breast cancer. Each received four cycles of standard doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously on day 1 every 3 weeks followed by four cycles of weekly paclitaxel (80 mg/m(2)) intravenously on days 1, 8, and 15, every 4 weeks. Concurrently with weekly paclitaxel, patients received either trastuzumab (4 mg/kg load, then 2 mg/kg intravenously) weekly until surgery, lapatinib (1250 mg orally) daily until surgery, or weekly trastuzumab plus lapatinib (750 mg orally) daily until surgery. After surgery, all patients received trastuzumab to complete 52 weeks of HER2-targeted therapy. Randomisation (ratio 1:1:1) was done centrally with stratification by clinical tumour size, clinical nodal status, hormone-receptor status, and age. The primary endpoint was the pathological complete response in the breast, and analysis was performed on an intention-to-treat population.Patient accrual started on July 16, 2007, and was completed on June 30, 2011; 529 women were enrolled in the trial. 519 patients had their pathological response determined. Breast pathological complete response was noted in 93 (52·5%, 95% CI 44·9-59·5) of 177 patients in the trastuzumab group, 91 (53·2%, 45·4-60·3) of 171 patients in the lapatinib group (p=0·9852); and 106 (62·0%, 54·3-68·8) of 171 patients in the combination group (p=0·095). The most common grade 3 and 4 toxic effects were neutropenia (29 [16%] patients in the trastuzumab group [grade 4 in five patients (3%), 28 [16%] in the lapatinib group [grade 4 in eight patients (5%)], and 29 [17%] in the combination group [grade 4 in nine patients (5%)]) and grade 3 diarrhoea (four [2%] patients in the trastuzumab group, 35 [20%] in the lapatinib group, and 46 [27%] in the combination group; p0·0001). Symptomatic congestive heart failure defined as New York Heart Association Class III or IV events occurred in seven (4%) patients in the trastuzumab group, seven (4%) in the lapatinib group, and one (1%) in the combination group; p=0·185).Substitution of lapatinib for trastuzumab in combination with chemotherapy resulted in similar high percentages of pathological complete response. Combined HER2-targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than single-agent HER2-directed therapy; these findings are consistent with results from other studies. Trials are being undertaken to further assess these findings in the adjuvant setting.

Study subjects were French-Canadian women with ductal carcinoma in situ (DCIS) or invasive breast cancer (incident or prevalent) who were treated and followed at a single breast cancer clinic affiliated with the Research Center of University of Montreal (CRCHUM), who were either aged less than 50 years at diagnosis or who were 50 years or older and with at least two affected first- or second-degree relatives. Subjects were tested for six founder mutations (three in BRCA1 and three in BRCA2); 1093 eligible cases were tested. Of these, 56 women (5.1%) were mutation carriers, including 43 BRCA2 carriers and 13 BRCA1 carriers. The prevalence of mutations was 5.3% for unselected women aged 50 and less and was 4.6% for familial cases over age 50. The prevalence of mutations was 3.3% for women with DCIS and was 5.3% for women with invasive cancer. It is rational to offer genetic testing to all French-Canadian women diagnosed recently or in the past with either DCIS or invasive breast cancer before age 50 or with familial breast cancer above age 50.

BACKGROUND: We lack comprehensive information about the extent of out-of-pocket costs after diagnosis of early breast cancer and their effects on the family's financial situation. METHODS: This longitudinal study assessed out-of-pocket costs and wage losses during the first year after diagnosis of early breast cancer among Canadian women and spouses. Out-of-pocket costs for treatments and follow-up, consultations with other practitioners, home help, clothing, and natural health products were estimated, with information collected from telephone interviews. Generalized linear models were used to identify women at risk of having higher costs and the effects of out-of-pocket costs on perceptions of the family's financial situation. RESULTS: Overall, 829 women (participation, 86.2%) and 391 spouses participated. Women's median net out-of-pocket costs during the year after diagnosis were $1002 (2003 Canadian dollars; mean = $1365; SD = $1238), and 74.4% of these costs resulted from treatments and follow-up. Spouses' median costs were $111 (mean = $234; SD = $320), or 9% of couples' total expenses. In multivariable analyses, the percentage of women with out-of-pocket costs of $1773 or more (upper quartile) was statistically significantly associated with higher education, working at diagnosis, living more than 50 km from the hospital where surgery was performed, and having two and three different types of adjuvant treatment (all 2-sided P values ≤ .01). However, when considered simultaneously with wage losses, out-of-pocket costs were not associated with perceived deterioration in the family's financial situation; rather, wage losses were the driving factor. CONCLUSIONS: Overall, out-of-pocket costs from breast cancer for the year after diagnosis are probably not unmanageable for most women. However, some women were at higher risk of experiencing financial burden resulting from these costs.

To estimate the 15-year survival following a diagnosis of stage I breast cancer among women who carry a BRCA1 mutation and to determine predictors of mortality, including the use of chemotherapy. Patients were 379 women with stage I breast cancer for whom a BRCA1 mutation had been identified, in herself or in a close family member. Patients were followed for up to 15 years from the initial diagnosis of breast cancer. Survival rates were estimated for women by age, tumor size (≤ 1 cm; > 1 cm), ER status (±), and by chemotherapy (yes/no). 42 women died of breast cancer in the follow-up period (11.2 %). Survival rates were similar for women with cancers of size 0-1.0 cm and size 1.1-2.0 cm. Of the 267 women in the study who used chemotherapy, 21 had died (7.9 %) compared to 21 deaths among 112 women who did not receive chemotherapy (18.8 %; p = 0.002). The 15-year survival was 89.4 % for women who received chemotherapy and was 73.1 % for women who did not receive chemotherapy (p = 0.08; log rank). The adjusted hazard ratio for death following a diagnosis of stage I breast cancer associated with chemotherapy was 0.53 (95 % CI 0.28-1.07; p value 0.06) after adjusting for age of diagnosis, tumor size, and estrogen receptor status. This was statistically significant only among women with ER-negative breast cancers (HR = 0.28; 95 % CI 0.10-0.79; p = 0.02). BRCA1 positive women who are treated for stage I breast cancer with chemotherapy have better survival than those who do not receive chemotherapy. The difference cannot be explained by other prognostic factors. All women with invasive breast cancer and a BRCA1 mutation should be considered to be candidates for chemotherapy.