Publications by authors named "André Robidoux"

72 Publications

Prognostic and predictive value of circulating tumor DNA during neoadjuvant chemotherapy for triple negative breast cancer.

Sci Rep 2020 09 7;10(1):14704. Epub 2020 Sep 7.

Lady Davis Institute, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.

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.
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http://dx.doi.org/10.1038/s41598-020-71236-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477566PMC
September 2020

NSABP B-41, a Randomized Neoadjuvant Trial: Genes and Signatures Associated with Pathologic Complete Response.

Clin Cancer Res 2020 08 5;26(16):4233-4241. Epub 2020 May 5.

NSABP Foundation, Pittsburgh, Pennsylvania.

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 , 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724952PMC
August 2020

The LISA randomized trial of a weight loss intervention in postmenopausal breast cancer.

NPJ Breast Cancer 2020 21;6. Epub 2020 Feb 21.

10Division of Medical Oncology & Hematology, Sunnybrook Odette Cancer Center, Ontario Clinical Oncology Group, University of Toronto, Toronto, ON Canada.

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/m 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,  = 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.
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http://dx.doi.org/10.1038/s41523-020-0149-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035359PMC
February 2020

Wage losses among spouses of women with nonmetastatic breast cancer.

Cancer 2020 03 10;126(5):1124-1134. Epub 2019 Dec 10.

Centre des Maladies du Sein (Center for Breast Diseases) CHU de Québec-Université Laval, Saint-Sacrement Hospital, Quebec City, Quebec, Canada.

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.
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http://dx.doi.org/10.1002/cncr.32638DOI Listing
March 2020

NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2.

J Clin Oncol 2020 02 10;38(5):444-453. Epub 2019 Dec 10.

NRG Oncology, Pittsburgh, PA.

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] 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; = .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; = .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; = .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.
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http://dx.doi.org/10.1200/JCO.19.01455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007289PMC
February 2020

NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2 breast cancer.

Breast Cancer Res 2019 12 3;21(1):133. Epub 2019 Dec 3.

NSABP Foundation, Inc., Nova Tower 2, Two Allegheny Center - Ste 1200, Pittsburgh, PA, 15212, USA.

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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.

Trials Registration: ClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.
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http://dx.doi.org/10.1186/s13058-019-1196-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892191PMC
December 2019

Axillary Lymph Node Ultrasound Following Neoadjuvant Chemotherapy in Biopsy-Proven Node-Positive Breast Cancer: Results from the SN FNAC Study.

Ann Surg Oncol 2019 Dec 11;26(13):4337-4345. Epub 2019 Oct 11.

Jewish General Hospital Segal Cancer Centre, McGill University, Montreal, QC, Canada.

Background: 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.

Methods: 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.

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.

Conclusion: 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.
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http://dx.doi.org/10.1245/s10434-019-07809-7DOI Listing
December 2019

A Unique Morphological Phenotype in Chemoresistant Triple-Negative Breast Cancer Reveals Metabolic Reprogramming and PLIN4 Expression as a Molecular Vulnerability.

Mol Cancer Res 2019 12 19;17(12):2492-2507. Epub 2019 Sep 19.

Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.

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.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0264DOI Listing
December 2019

Pathologic complete response and outcomes by intrinsic subtypes in NSABP B-41, a randomized neoadjuvant trial of chemotherapy with trastuzumab, lapatinib, or the combination.

Breast Cancer Res Treat 2019 Nov 19;178(2):389-399. Epub 2019 Aug 19.

National Surgical Adjuvant Breast and Bowel Project (NSABP), Nova Tower 2, 100 Allegheny Square, Pittsburgh, PA, 15212, USA.

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 < 0.001). In multivariate analysis among patients receiving trastuzumab-containing regimens (with clinical factors and HER2E subtype as factors), HER2E subtype was most strongly associated with pCR [OR 8.41 (95% CI 2.52-28.1) p < 0.001]. Patients with HER2E tumors did not benefit more from dual HER2-targeted therapy versus trastuzumab. The pCR rate was higher among HER2E tumors versus other subtypes in both estrogen receptor-positive and -negative tumors (p ≤ 0.001). Higher ESR1 gene expression was associated with lower pCR rate. No association was observed between subtype and long-term outcomes.

Conclusion: Patients with HER2E tumors were most likely to attain pCR versus other subtypes. HER2E subtype represents a favorable marker for predicting HER2-targeting benefit, particularly with trastuzumab-based therapies.
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http://dx.doi.org/10.1007/s10549-019-05398-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797698PMC
November 2019

Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial.

J Clin Oncol 2019 01 6;37(3):178-189. Epub 2018 Dec 6.

15 National Surgical Adjuvant Breast and Bowel Project Foundation, Pittsburgh, PA.

Purpose: CDK4/6 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 Methods: Postmenopausal 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.

Results: Three 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.

Conclusion: Adding 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.
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http://dx.doi.org/10.1200/JCO.18.01624DOI Listing
January 2019

Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial.

J Clin Oncol 2018 04 14;36(11):1073-1079. Epub 2018 Feb 14.

Irene L. Wapnir, Stanford University School of Medicine, Stanford, CA; Karen N. Price and Shari Gelber, Frontier Science and Technology Research Foundation, Richard D. Gelber, Frontier Science and Technology Research Foundation, Dana-Farber Cancer Institute, Harvard TH Chan School of Public Health, Harvard Medical School, Meredith M. Regan, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Stewart J. Anderson, University of Pittsburgh Graduate School of Public Health; Priya Rastogi, University of Pittsburgh Cancer Institute; Norman Wolmark, Allegheny Health Network Cancer Institute, Pittsburgh, PA; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec; Alexander H.G. Paterson, Tom Baker Cancer Centre, Calgary, Alberta, Canada; Miguel Martín, CIBERONC, Instituto de Investigación Sanitaria Gregorio Marañon, Universidad Complutense, Madrid; José Manuel Baena-Cañada, Hospital Puerta del Mar, Cádiz, Spain; Johan W.R. Nortier, Leids Universitair Medisch Centrum, Leiden, Netherlands; Mothaffar F. Rimawi, Duncan Comprehensive Cancer Center at Baylor College of Medicine, Houston, TX; István Láng, National Institute of Oncology, Budapest, Hungary; Beat Thürlimann, Kantonsspital, St. Gallen; Stefan Aebi, Lucerne Cantonal Hospital and University of Bern, Switzerland; Eleftherios P. Mamounas, Orlando Health University of Florida Health Cancer Center, Orlando, FL; Charles E. Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; and Alan S. Coates, University of Sydney, Sydney, Australia.

Purpose Isolated locoregional recurrence (ILRR) predicts a high risk of developing breast cancer distant metastases and death. The Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial investigated the effectiveness of chemotherapy (CT) after local therapy for ILRR. A report at 5 years of median follow-up showed significant benefit of CT for estrogen receptor (ER)-negative ILRR, but additional follow-up was required in ER-positive ILRR. Patients and Methods CALOR was an open-label, randomized trial for patients with completely excised ILRR after unilateral breast cancer. Eligible patients were randomly assigned to receive CT or no CT and stratified by prior CT, hormone receptor status, and location of ILRR. Patients with hormone receptor-positive ILRR received adjuvant endocrine therapy. Radiation therapy was mandated for patients with microscopically involved margins, and anti-human epidermal growth factor receptor 2 therapy was optional. End points were disease-free survival (DFS), overall survival, and breast cancer-free interval. Results From August 2003 to January 2010, 162 patients were enrolled: 58 with ER-negative and 104 with ER-positive ILRR. At 9 years of median follow-up, 27 DFS events were observed in the ER-negative group and 40 in the ER-positive group. The hazard ratios (HR) of a DFS event were 0.29 (95% CI, 0.13 to 0.67; 10-year DFS, 70% v 34%, CT v no CT, respectively) in patients with ER-negative ILRR and 1.07 (95% CI, 0.57 to 2.00; 10-year DFS, 50% v 59%, respectively) in patients with ER-positive ILRR ( P = .013). HRs were 0.29 (95% CI, 0.13 to 0.67) and 0.94 (95% CI, 0.47 to 1.85), respectively, for breast cancer-free interval ( P = .034) and 0.48 (95% CI, 0.19 to 1.20) and 0.70 (95% CI, 0.32 to 1.55), respectively, for overall survival ( P = .53). Results for the three end points were consistent in multivariable analyses adjusting for location of ILRR, prior CT, and interval from primary surgery. Conclusion The final analysis of CALOR confirms that CT benefits patients with resected ER-negative ILRR and does not support the use of CT for ER-positive ILRR.
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http://dx.doi.org/10.1200/JCO.2017.76.5719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891132PMC
April 2018

Comparative Evaluation of Iodine-125 Radioactive Seed Localization and Wire Localization for Resection of Breast Lesions.

Can Assoc Radiol J 2017 Nov 15;68(4):447-455. Epub 2017 Sep 15.

Breast Imaging Center, Department of Radiology, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada. Electronic address:

Purpose: Radioactive seed localization (RSL) uses a titanium seed labeled with iodine-125 energy for surgery of nonpalpable breast lesions. RSL facilitates radiology-surgery scheduling and allows for improved oncoplasty compared with wire localization (WL). The purpose of this work was to compare the 2 techniques.

Methods: We performed a retrospective study of all breast lesions operated with RSL between February 2013 and March 2015 at our university institution, and compared with an equivalent number of surgeries performed with a single WL. Imaging and pathology reports were reviewed for information on guidance mode, accuracy of targeting, nature of excised lesion, size and volume of surgical specimen, status of margins, and reinterventions.

Results: A total of 254 lesions (247 women) were excised with RSL and compared with 257 lesions (244 women) whose surgery was guided by WL. Both groups were comparable in lesion pathology, guidance mode for RSL or WL positioning, and accuracy of targeting (98% correct). Mean delay between biopsy and surgery was 84 days for RSL versus 103 after WL (P = .04). No differences were noted after RSL or WL for surgical specimen mean weight, largest diameter, and volume excised. For malignancies, the rate of positive margins was comparable (2.8%-3%), with 5 of 10 women in the RSL group who underwent a second surgery displaying residual malignancy compared with 3 of 9 women in the WL group.

Conclusions: RSL is safe and accurate, and has comparable surgical endpoints to WL. Because RSL offers flexible scheduling and facilitated oncoplasty, RSL may replace WL for resection of nonpalpable single breast lesions.
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http://dx.doi.org/10.1016/j.carj.2017.04.006DOI Listing
November 2017

The identification of challenges in tissue collection for biomarker studies: the Q-CROC-03 neoadjuvant breast cancer translational trial experience.

Mod Pathol 2017 11 28;30(11):1567-1576. Epub 2017 Jul 28.

Department of Oncology, Lady Davis Institute, McGill University, Montreal, QC, Canada.

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 <50% tumor content. After chemotherapy, 30% of biopsy or surgical samples in patients with incomplete response did not contain any tumor. Finally, RNA-later not only made histopathological assessment of tumor content difficult, but yielded less DNA than fresh snap frozen samples. We recommend that high-quality tissue procurement can be best accomplished if at least three image-guided core biopsies be obtained per sample, each of these cores be examined for tumor cellularity and that at least some of them be freshly snap frozen in liquid nitrogen.
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http://dx.doi.org/10.1038/modpathol.2017.82DOI Listing
November 2017

Limitations of Personalized Medicine and Gene Assays for Breast Cancer.

Cureus 2017 Mar 17;9(3):e1100. Epub 2017 Mar 17.

Department of Radiation Oncology, Centre Hospitalier de l'Université de Montréal (CHUM).

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.
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http://dx.doi.org/10.7759/cureus.1100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393908PMC
March 2017

Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: A multicenter trial.

J Surg Oncol 2017 Jun 13;115(8):917-923. Epub 2017 Apr 13.

Genomic Health, Inc., Redwood City, California.

Objective: We hypothesized that the Oncotype Dx 21-gene Recurrence Score (RS) could guide neoadjuvant systemic therapy (NST) to facilitate breast conserving surgery (BCS) for hormone receptor positive (HR+) breast cancers.

Methods: This study enrolled patients with HR+, HER2-negative, invasive breast cancers not suitable for BCS (size ≥ 2 cm). Core needle biopsy blocks were tested. For tumors with RS < 11, patients received hormonal therapy (NHT); patients with RS > 25 tumors received chemotherapy (NCT); patients with RS 11-25 were randomized to NHT or NCT. Primary endpoint was whether 1/3 or more of randomized patients refused assigned treatment.

Results: Sixty-four patients were enrolled. Of 33 patients with RS 11-25, 5 (15%) refused assignment to NCT. This was significantly lower than the 33% target (binomial test, P = 0.0292). Results for clinical outcomes (according to treatment received for 55 subjects) included successful BCS for 75% of tumors with RS < 11 receiving NHT, 72% for RS 11-25 receiving NHT, 64% for RS 11-25 receiving NCT, and 57% for RS > 25 receiving NCT.

Conclusions: Using the RS to guide NST is feasible. These results suggest that for patients with RS < 25 NHT is a potentially effective strategy.
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http://dx.doi.org/10.1002/jso.24610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481477PMC
June 2017

The Effect on Surgical Complications of Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer: NRG Oncology/NSABP Protocol B-40.

Ann Surg Oncol 2017 Jul 18;24(7):1853-1860. Epub 2016 Nov 18.

NRG Oncology and the National Surgical Adjuvant Breast and Bowel Project (NSABP) (NSABP legacy trials are now part of the NRG Oncology portfolio), Pittsburgh, PA, USA.

Background: NRG 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.

Methods: A 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 (15 mg/kg every 3 weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24 months following study entry.

Results: Early 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 (<1%). Among 193 patients undergoing expander or implant reconstructions, 19 (19.6%) of 97 in the bev-receiving group versus 10 (10.4%) of 96 in the non-bev group had grade ≥3 complications (Pearson, p = 0.11).

Conclusions: Overall, adding bev increased surgical complications, but most serious complications were not significantly increased. In particular, the need for surgical intervention in patients undergoing breast reconstruction with prosthetic implants was higher with bev but was not statistically significantly different. With precautions, bev can be used safely perioperatively in patients undergoing surgery for breast cancer.
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http://dx.doi.org/10.1245/s10434-016-5662-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821429PMC
July 2017

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5.

Clin Breast Cancer 2017 02 28;17(1):48-54.e3. Epub 2016 Jul 28.

National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, Pittsburgh, PA; Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA.

Background: The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC).

Patients And Methods: Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m) followed by 4 cycles of docetaxel (100 mg/m). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met.

Results: A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively.

Conclusion: The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations.
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http://dx.doi.org/10.1016/j.clbc.2016.07.008DOI Listing
February 2017

Poor Prognosis After Second Locoregional Recurrences in the CALOR Trial.

Ann Surg Oncol 2017 Feb 23;24(2):398-406. Epub 2016 Sep 23.

IBCSG, Luzerner Kantonsspital, Lucerne and University of Berne, Switzerland and Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland.

Background: Isolated locoregional recurrences (ILRRs) of breast cancer confer a significant risk for the development of distant metastasis. Management practices and second ILRR events in the Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial were investigated.

Methods: In this study, 162 patients with ILRR were randomly assigned to receive postoperative chemotherapy or no chemotherapy. Descriptive statistics characterize outcomes according to local therapy and the influence of hormone receptor status on subsequent recurrences. Competing risk regression models, Kaplan-Meier estimates, and Cox proportional hazards models were used to evaluate associations between treatment, site of second recurrence, and outcome.

Results: The median follow-up period was 4.9 years. Of the 98 patients who received breast-conserving primary surgery 89 had an ipsilateral-breast tumor recurrence. Salvage mastectomy was performed for 73 patients and repeat lumpectomy for 16 patients. Another eight patients had nodal ILRR, and one patient had chest wall ILRR. Among 64 patients whose primary surgery was mastectomy, 52 had chest wall/skin ILRR, and 12 had nodal ILRR. For 15 patients, a second ILRR developed a median of 1.6 years (range 0.08-4.8 years) after ILRR. All second ILRRs occurred for patients with progesterone receptor-negative ILRR. Death occurred for 7 (47 %) of 15 patients with a second ILRR and 19 (51 %) of 37 patients with a distant recurrence. As shown in the multivariable analysis, the significant predictors of survival after either a second ILRR or distant recurrence were chemotherapy for the primary cancer (hazard ratio [HR], 3.55; 95 % confidence interval [CI], 1.15-10.9; p = 0.03) and the interval (continuous) from the primary surgery (HR, 0.87; 95 % CI, 0.75-1.00; p = 0.05).

Conclusions: Second ILRRs represented about one third of all recurrence events after ILRR, and all were PR-negative. These second ILRRs and distant metastases portend an unfavorable outcome.
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http://dx.doi.org/10.1245/s10434-016-5571-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215961PMC
February 2017

Frequency adaptation for enhanced radiation force amplitude in dynamic elastography.

IEEE Trans Ultrason Ferroelectr Freq Control 2015 Aug;62(8):1453-66

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.
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http://dx.doi.org/10.1109/TUFFC.2015.007023DOI Listing
August 2015

Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial.

Lancet Oncol 2015 Sep 10;16(9):1037-1048. Epub 2015 Aug 10.

National Surgical Adjuvant Breast and Bowel Project (NSABP/NRG Oncology), Pittsburgh, PA, USA; Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA, USA.

Background: NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively.

Methods: In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m(2)) with addition of capecitabine (825 mg/m(2) oral twice daily days 1-14, 75 mg/m(2) docetaxel) or with addition of gemcitabine (1000 mg/m(2) days 1 and 8 intravenously, 75 mg/m(2) docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m(2) and 600 mg/m(2) intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408.

Findings: Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%]).

Interpretation: The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent.

Funding: National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.
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http://dx.doi.org/10.1016/S1470-2045(15)00041-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624323PMC
September 2015

Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9.

Breast Cancer Res Treat 2015 Jul 1;152(2):399-405. Epub 2015 Jul 1.

NSABP Foundation, Inc., Nova Tower 2, Two Allegheny Center, 12th Flr., Pittsburgh, PA, 15212, USA.

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.
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http://dx.doi.org/10.1007/s10549-015-3466-4DOI Listing
July 2015

The Added Value of Statistical Modeling of Backscatter Properties in the Management of Breast Lesions at US.

Radiology 2015 Jun 12;275(3):666-74. Epub 2014 Dec 12.

From the Department of Radiology, Breast Imaging Center (I.T., M.E.K.), Department of Surgical Oncology, Breast Care Center (A.R.), and Department of Pathology (L.G.), Centre Hospitalier de l'Université de Montréal, 3840 Saint-Urbain, Montreal, QC, Canada H2W 1T8; Department of Radiology, Radio-Oncology and Nuclear Medicine (I.T., M.E.K., G.C.) and Institute of Biomedical Engineering (G.C.), Université de Montréal, Montreal, Quebec, Canada; and Laboratory of Biorheology and Medical Ultrasonics, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada (F.D., L.A., B.C., G.C.).

Purpose: To develop a classification method based on the statistical backscatter properties of tissues that can be used as an ancillary tool to the usual Breast Imaging Reporting and Data System (BI-RADS) classification for solid breast lesions identified at ultrasonography (US).

Materials And Methods: This study received institutional review board approval, and all subjects provided informed consent. Eighty-nine women (mean age, 50 years; age range, 22-82 years) with 96 indeterminate solid breast lesions (BI-RADS category 4-5; mean size, 13.2 mm; range, 2.6-44.7 mm) were enrolled. Prior to biopsy, additional radiofrequency US images were obtained, and a 3-second cine sequence was used. The research data were analyzed at a later time and were not used to modify patient management decisions. The lesions were segmented manually, and parameters of the homodyned K distribution (α, k, and μn values) were extracted for three regions: the intratumoral zone, a 3-mm supratumoral zone, and a 5-mm infratumoral zone. The Mann-Whitney rank sum test was used to identify parameters with the best discriminating value, yielding intratumoral α, supratumoral k, and infratumoral μn values.

Results: The 96 lesions were classified as follows: 48 BI-RADS category 4A lesions, 16 BI-RADS category 4B lesions, seven BI-RADS category 4C lesions, and 25 BI-RADS category 5 lesions. There were 24 cancers (25%). The area under the receiver operating characteristic curve was 0.76 (95% confidence interval: 0.65, 0.86). Overall, 24% of biopsies (in 17 of 72 lesions) could have been spared. By limiting analysis to lesions with a lower likelihood of malignancy (BI-RADS category 4A-4B), this percentage increased to 26% (16 of 62 lesions). Among benign lesions, the model was used to correctly classify 10 of 38 fibroadenomas (26%) and three of seven stromal fibroses (43%).

Conclusion: The statistical model performs well in the classification of solid breast lesions at US, with the potential of preventing one in four biopsies without missing any malignancy.
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http://dx.doi.org/10.1148/radiol.14140318DOI Listing
June 2015

Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study.

J Clin Oncol 2015 Jan 1;33(3):258-64. Epub 2014 Dec 1.

Jean-Francois Boileau, Mark Basik, and Andre Lisbona, Montreal Jewish General Segal Cancer Centre, McGill University; Louis Gaboury, Isabelle Trop, Rami J. Younan, Erica Patocskai, and Andre Robidoux, Centre Hospitalier de l'Universite de Montreal; Lucas Sideris, Hopital Maisonneuve Rosemont, Universite de Montreal; Sarkis Meterissian and Atilla Omeroglu, McGill University Health Centre, Montreal; Brigitte Poirier and Louise Provencher, Hopital Saint-Sacrement, Universite Laval, Quebec City, Quebec; Claire M.B. Holloway and Frances C. Wright, Sunnybrook Odette Cancer Centre, University of Toronto; David R. McCready, University Health Network, University of Toronto, Toronto; Angel Arnaout, Ottawa Hospital, University of Ottawa, Ottawa; Muriel Brackstone, London Regional Cancer Program, University of Western Ontario, London, Ontario, Canada; and Stephen E. Karp, Lahey Hospital and Medical Center, Tufts University School of Medicine, Boston, MA.

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.
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http://dx.doi.org/10.1200/JCO.2014.55.7827DOI Listing
January 2015

Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.

Breast Cancer Res Treat 2014 Jul 21;146(2):421-7. Epub 2014 Jun 21.

Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

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.
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http://dx.doi.org/10.1007/s10549-014-3026-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131437PMC
July 2014

Randomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: the LISA trial.

J Clin Oncol 2014 Jul 16;32(21):2231-9. Epub 2014 Jun 16.

Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Princess Margaret Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Center; Pamela J. Goodwin and Kathleen I. Pritchard, University of Toronto, Toronto; Roanne J. Segal, Ottawa Hospital Regional Cancer Center, University of Ottawa, Ottawa; Gregory R. Pond, Som Mukherjee, and Mark Levine, Juravinski Hospital and Cancer Center; Brian Findlay, Niagara Health System, Walker Family Cancer Center; Gregory R. Pond, Mark Levine, Brian Findlay, and Som Mukherjee, McMaster University, Hamilton, Ontario; Michael Vallis, Dalhousie University, Halifax, Nova Scotia; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Jennifer A. Ligibel, Dana-Farber Cancer Institute; George L. Blackburn, Beth Israel Deaconess Medical Center; Jennifer A. Ligibel and George L. Blackburn, Harvard Medical School, Boston, MA; and Julie R. Gralow, University of Washington, Seattle, WA.

Purpose: Obesity is associated with poor outcomes in women with operable breast cancer. Lifestyle interventions (LIs) that help women reduce their weight may improve outcomes.

Patients And Methods: We conducted a multicenter randomized trial comparing mail-based delivery of general health information alone or combined with a 24-month standardized, telephone-based LI that included diet (500 to 1,000 kcal per day deficit) and physical activity (150 to 200 minutes of moderate-intensity physical activity per week) goals to achieve weight loss (up to 10%). Women receiving adjuvant letrozole for T1-3N0-3M0 breast cancer with a body mass index (BMI) ≥ 24 kg/m(2) were eligible. Weight was measured in the clinic, and self-report physical activity, quality-of-life (QOL), and diet questionnaires were completed. The primary outcome was disease-free survival. Accrual was terminated at 338 of 2,150 planned patients because of loss of funding.

Results: Mean weight loss was significantly (P < .001) greater in the LI arm versus the comparison arm (4.3 v 0.6 kg or 5.3% v 0.7% at 6 months and 3.1 v 0.3 kg or 3.6% v 0.4% at 24 months) and occurred consistently across strata (BMI 24 to < 30 v ≥ 30 kg/m(2); prior v no prior adjuvant chemotherapy). Weight loss was greatest in those with higher baseline levels of moderate-intensity physical activity or improvement in QOL. Hospitalization rates and medical events were similar.

Conclusion: A telephone-based LI led to significant weight loss that was still evident at 24 months, without adverse effects on QOL, hospitalizations, or medical events. Adequately powered randomized trials with cancer end points are needed.
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http://dx.doi.org/10.1200/JCO.2013.53.1517DOI Listing
July 2014

Randomised, phase II, placebo-controlled, trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone-receptor-positive metastatic breast cancer (MBC): the OCOG ZAMBONEY study.

Breast Cancer Res Treat 2014 Jul 13;146(1):153-62. Epub 2014 Jun 13.

Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa Hospital Research Institute and University of Ottawa, Box 912, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada,

Biomarkers of bone turnover, including urine N-telopeptide (uNTx), have been used as surrogate measures of response to bone-targeted therapies. Vascular endothelial growth factor (VEGF) levels correlate with extent of bone metastases. We assessed whether vandetanib, an inhibitor of VEGF, epidermal growth factor receptor and RET signalling, improved uNTx response when added to fulvestrant (F) in breast cancer patients with bone metastases. Postmenopausal patients with bone predominant, hormone-receptor-positive metastatic breast cancer were randomised to F (500 mg IM days 1, 15, 29, then monthly) with either vandetanib (100 mg PO OD) (FV) or placebo (FP). The primary objective was uNTx response. Secondary objectives included PFS, OS, RECIST response, pain scores and toxicity. Sixty-one patients were allocated to FV and 68 to FP. Out of 127 analyzable patients, an uNTx response occurred in 66 % for FV and 54 % for FP (p = 0.21). No difference was detected between groups for PFS; HR = 0.95 (95 % CI 0.65-1.38) or OS HR = 0.69 (95 % CI 0.37-1.31). For the 62 patients with measurable disease, clinical benefit rates were 41 and 43 %, respectively (p = 0.47). Serious adverse events were similar, 3.3 % for FV versus 5.9 % for FP. Elevated baseline uNTx (>65 nM BCE/mmol Cr) was prognostic for PFS, HR = 1.55 (95 % CI 1.04-2.30) and for OS, HR = 2.32 (95 % CI 1.25-4.33). The addition of vandetanib to fulvestrant did not improve biomarker response, PFS or OS in patients with bone metastases. Baseline bone turnover was prognostic for PFS and OS.
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http://dx.doi.org/10.1007/s10549-014-3015-6DOI Listing
July 2014

Validating the content of a brief informational intervention to empower patients and spouses facing breast cancer: perspectives of both couple members.

J Cancer Surviv 2014 Sep 27;8(3):508-20. Epub 2014 Apr 27.

Département de psychologie, Université du Québec à Trois-Rivières, Trois-Rivières, Canada.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Implications For Cancer Survivors: Couples approved of the idea of being guided in their adjustment to breast cancer. However, the message format requires adaptation and further testing.
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http://dx.doi.org/10.1007/s11764-014-0359-1DOI Listing
September 2014

Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial.

Lancet Oncol 2014 Feb 16;15(2):156-63. Epub 2014 Jan 16.

Stanford University School of Medicine, Stanford, CA, USA.

Background: Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients.

Methods: The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152.

Findings: From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection.

Interpretation: Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative.

Funding: US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).
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http://dx.doi.org/10.1016/S1470-2045(13)70589-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982874PMC
February 2014