Publications by authors named "Melissa E Hughes"

41 Publications

Genomic Characterization of Metastatic Breast Cancer.

Clin Cancer Res 2021 Feb 8;27(4):1105-1118. Epub 2020 Dec 8.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: In contrast to recurrence after initial diagnosis of stage I-III breast cancer [recurrent metastatic breast cancer (rMBC)], metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS).

Experimental Design: Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC.

Results: When comparing primary tumors by subtype, amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, = 0.0005, = 0.111). Mutations in , and were more prevalent, and and less prevalent, in primary HR/HER2 tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; = 0.008, = 0.107), MYC (79.7 vs. 23.3 months; = 0.0003, = 0.011), and cell-cycle (122.7 vs. 54.9 months; = 0.034, = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC ( = 0.041).

Conclusions: Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887078PMC
February 2021

TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.

J Clin Oncol 2020 Dec 29;38(36):4274-4282. Epub 2020 Oct 29.

Harvard Medical School, Boston, MA.

Purpose: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g)/ mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)/ mutations or g/s mutations in homologous recombination (HR)-related genes other than 2.

Methods: Eligible patients had MBC with measurable disease and germline mutations in non-/ HR-related genes (cohort 1) or somatic mutations in these genes or / (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).

Results: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in s/, or . In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g (ORR, 82%) and s/ (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for g and 6.3 months (90% CI, 4.4 months to NA) for s/ mutation carriers. No responses were observed with or mutations alone.

Conclusion: PARP inhibition is an effective treatment for patients with MBC and g or s/ mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g/ mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.
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http://dx.doi.org/10.1200/JCO.20.02151DOI Listing
December 2020

Identifying Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials.

JCO Precis Oncol 2019 15;3. Epub 2019 Nov 15.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling.

Patients And Methods: Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877). Our primary aim was to describe the proportion of patients with a qualifying mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of mutations, and survival. Associations were calculated using Fisher's exact test.

Results: We identified a total of 1,045 patients with metastatic breast cancer without amplification who had available genomic testing results. Of these, 42 patients were found to have mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing.

Conclusion: More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies.
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http://dx.doi.org/10.1200/PO.19.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446367PMC
November 2019

Association between the 21-gene recurrence score and isolated locoregional recurrence in stage I-II, hormone receptor-positive breast cancer.

Radiat Oncol 2020 Aug 17;15(1):198. Epub 2020 Aug 17.

Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, USA.

Background: Although the 21-gene recurrence score (RS) assay is widely used to predict distant recurrence risk and benefit from adjuvant chemotherapy among women with hormone receptor-positive (HR+) breast cancer, the relationship between the RS and isolated locoregional recurrence (iLRR) remains poorly understood. Therefore, we examined the association between the RS and risk of iLRR for women with stage I-II, HR+ breast cancer.

Methods: We identified 1758 women captured in the national prospective Breast Cancer-Collaborative Outcomes Research Database who were diagnosed with stage I-II, HR+ breast cancer from 2006 to 2012, treated with mastectomy or breast-conserving surgery, and received RS testing. Women who received neoadjuvant therapy were excluded. The association between the RS and risk of iLRR was examined using competing risks regression.

Results: Overall, 19% of the cohort (n = 329) had a RS ≥25. At median follow-up of 29 months, only 22 iLRR events were observed. Having a RS ≥25 was not associated with a significantly higher risk of iLRR compared to a RS < 25 (hazard ratio 1.14, 95% confidence interval 0.39-3.36, P = 0.81). When limited to women who received adjuvant endocrine therapy without chemotherapy (n = 1199; 68% of the cohort), having a RS ≥25 (n = 74) was significantly associated with a higher risk of iLRR compared to a RS < 25 (hazard ratio 3.66, 95% confidence interval 1.07-12.5, P = 0.04). In this group, increasing RS was associated with greater risk of iLRR (compared to RS < 18, hazard ratio of 1.66, 3.59, and 7.06, respectively, for RS 18-24, 25-30, and ≥ 31; P = 0.02).

Conclusions: The RS was significantly associated with risk of iLRR in patients who did not receive adjuvant chemotherapy. The utility of the RS in identifying patients who have a low risk of iLRR should be further studied.
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http://dx.doi.org/10.1186/s13014-020-01640-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429461PMC
August 2020

Barriers to Clinical Trial Accrual: Perspectives of Community-Based Providers.

Clin Breast Cancer 2020 10 7;20(5):395-401.e3. Epub 2020 May 7.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. Electronic address:

Background: Only a small proportion of patients with cancer enroll onto clinical trials. Previous studies have explored patient-related barriers to trial participation; however, few studies have focused on the provider perspective. We aimed to describe referral practices and barriers to referrals of patients with breast cancer for clinical trials, including the utilization of web-based trial-matching tools.

Materials And Methods: In 2016, we distributed 120 surveys to attendees of a breast oncology continuing medical education course. The survey addressed referral patterns, trial knowledge, and perceptions of web-based trial-matching tools. After survey completion, participants were provided a link to the Dana-Farber Cancer Institute trial-matching tool. Three months later, a follow-up survey was sent to assess their use of this tool. Descriptive statistics were used to summarize survey data.

Results: Ninety-six (80%) participants completed the first survey; 5 respondents did not actively treat patients with breast cancer and were excluded. Respondents included medical (30%) and surgical (22%) oncologists, nurse practitioners/physician assistants (26%), and other (22%). Neoadjuvant and metastatic trials were deemed the highest priority. The primary reported barriers included perceived lack of patient interest, lack of trial awareness, and logistical barriers. Emailing trial investigators directly was the preferred method of trial referral. Although 80% indicated that web-based tools would increase trial referrals, our follow-up survey revealed that only 18% of respondents used our web-based tool.

Conclusion: Our respondents valued trial participation for their patients but found it difficult to manage. Further research is needed regarding how to increase the likelihood that patients are presented with appropriate trial options.
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http://dx.doi.org/10.1016/j.clbc.2020.05.001DOI Listing
October 2020

The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

Cancer Discov 2020 Aug 13;10(8):1174-1193. Epub 2020 May 13.

Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including loss, activating alterations in , and , and loss of estrogen receptor expression. experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired , or alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in , and -have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR metastatic breast cancer..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1390DOI Listing
August 2020

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

Clin Cancer Res 2020 06 13;26(11):2556-2564. Epub 2020 Mar 13.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.

Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.

Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( = 13/16) in newly diagnosed MBC, 23% ( = 7/30) at postoperative and 19% ( = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months).

Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654718PMC
June 2020

Subtype switching in breast cancer brain metastases: a multicenter analysis.

Neuro Oncol 2020 08;22(8):1173-1181

Computational Neuroscience Outcomes Center, Department of Neurosurgery, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Breast cancer (BC) brain metastases (BM) can have discordant hormonal or human epidermal growth factor receptor 2 (HER2) expression compared with corresponding primary tumors. This study aimed to describe incidence, predictors, and survival outcomes of discordant receptors and associated subtype switching in BM.

Methods: BCBM patients seen at 4 tertiary institutions who had undergone BM resection or biopsy were included. Surgical pathology reports were retrospectively assessed to determine discordance between the primary tumor and the BCBM. In discordant cases, expression in extracranial metastases was also assessed.

Results: In BM from 219 patients, prevalence of any discordance was 36.3%; receptor-specific discordance was 16.7% for estrogen, 25.2% for progesterone, and 10.4% for HER2. Because estrogen and progesterone were considered together for hormonal status, 50 (22.8%) patients switched subtype as a result; 20 of these switches were HER2 based. Baseline subtype predicted switching, which occurred in up to 37.5% of primary HR+ patients. Moreover, 14.8% of initially HER2-negative patients gained HER2 in the BM. Most (63.6%) discordant patients with extracranial metastases also had discordance between BM and extracranial subtype. Loss of receptor expression was generally associated with worse survival, which appeared to be driven by estrogen loss (hazard ratio = 1.80, P = 0.03). Patients gaining HER2 status (n = 8) showed a nonsignificant tendency toward improved survival (hazard ratio = 0.64, P = 0.17).

Conclusions: In this multicenter study, we report incidence and predictors of subtype switching, the risk of which varies considerably by baseline subtype. Switches can have clinical implications for prognosis and treatment choice.
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http://dx.doi.org/10.1093/neuonc/noaa013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471502PMC
August 2020

Impact of Residual Nodal Disease Burden on Technical Outcomes of Sentinel Lymph Node Biopsy for Node-Positive (cN1) Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

Ann Surg Oncol 2019 Nov 20;26(12):3846-3855. Epub 2019 Jun 20.

Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.

Background: Recent trials have demonstrated the feasibility of sentinel lymph node biopsy (SLNB) for cN1 breast cancer patients after neoadjuvant chemotherapy (NAC). This study evaluated the technical outcomes of SLNB by residual nodal disease volume.

Methods: From a prospective database, cT1-3 cN1 patients receiving NAC and surgery from 2016 to 2017 were identified. Performance measures of post-NAC physical exam and imaging-based axillary assessment were compared. For the patients who converted to cN0 and underwent SLNB, adequate mapping (defined as ≥ 3 SLN) and the false-negative rate (FNR) of intraoperative SLN evaluation were assessed by residual nodal disease volume (ypN1-3 vs ypN0[i+]/ypN1mi vs ypN0).

Results: Of 156 cT1-3 cN1 patients, 96 converted to cN0 and underwent SLNB. Adequate mapping was achieved for 64 patients (66.7%) and was not associated with nodal volume (p = 0.12). The FNR of the intraoperative SLN evaluation was 37.8%, and smaller nodal volume was associated with FNR (p < 0.01). Of 36 patients (37.5%) who achieved an axillary pathologic complete response, 24 (66.7%) had three or more negative SLNs and were safely spared axillary lymph node dissection (ALND). The positive predictive values of physical exam versus imaging-based post-NAC nodal assessment were respectively 88% and 69.8%.

Conclusions: This study showed SLNB to be an effective tool for minimizing axillary surgery in cN1 patients treated with NAC. However, important technical limitations exist, such as inability to identify three SLNs in more than two-thirds of patients and high-false negative rates for intraoperative SLN evaluation, particularly for patients with small residual nodal volumes. Preoperative counseling should include realistic assessment of the potential need for ALND in this population.
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http://dx.doi.org/10.1245/s10434-019-07515-4DOI Listing
November 2019

Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.

Oncologist 2019 07 5;24(7):e441-e449. Epub 2018 Dec 5.

Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Background: The diagnosis of mixed invasive ductal and lobular carcinoma (IDC-L) in clinical practice is often associated with uncertainty related to its prognosis and response to systemic therapies. With the increasing recognition of invasive lobular carcinoma (ILC) as a distinct disease subtype, questions surrounding IDC-L become even more relevant. In this study, we took advantage of a detailed clinical database to compare IDC-L and ILC regarding clinicopathologic and treatment characteristics, prognostic power of histologic grade, and survival outcomes.

Materials And Methods: In this retrospective cohort study, we identified 811 patients diagnosed with early-stage breast cancer with IDC-L or ILC. Descriptive statistics were performed to compare baseline clinicopathologic characteristics and treatments. Survival rates were subsequently analyzed using the Kaplan-Meier method and compared using the Cox proportional hazards model.

Results: Patients with ILC had more commonly multifocal disease, low to intermediate histologic grade, and HER2-negative disease. Histologic grade was prognostic for patients with IDC-L but had no significant discriminatory power in patients with ILC. Among postmenopausal women, those with IDC-L had significantly better outcomes when compared with those with ILC: disease-free survival (DFS) and overall survival (OS; adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.31-0.95). Finally, postmenopausal women treated with an aromatase inhibitor had more favorable DFS and OS than those treated with tamoxifen only (OS adjusted HR, 0.50; 95% CI, 0.29-0.87), which was similar for both histologic types ( = .212).

Conclusion: IDC-L tumors have a better prognosis than ILC tumors, particularly among postmenopausal women. Histologic grade is an important prognostic factor in IDC-L but not in ILC.

Implications For Practice: This study compared mixed invasive ductal and lobular carcinoma (IDC-L) with invasive lobular carcinomas (ILCs) to assess the overall prognosis, the prognostic role of histologic grade, and response to systemic therapy. It was found that patients with IDC-L tumors have a better prognosis than ILC, particularly among postmenopausal women, which may impact follow-up strategies. Moreover, although histologic grade failed to stratify the risk of ILC, it showed an important prognostic power in IDC-L, thus highlighting its clinical utility to guide treatment decisions of IDC-L. Finally, the disease-free survival advantage of adjuvant aromatase inhibitors over tamoxifen in ILC was consistent in IDC-L.
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http://dx.doi.org/10.1634/theoncologist.2018-0363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656459PMC
July 2019

Unraveling the clinicopathological features driving the emergence of mutations in metastatic breast cancer.

NPJ Breast Cancer 2018 2;4:22. Epub 2018 Aug 2.

2Department of Medical Oncology, Dana Farber-Cancer Institute, Boston, MA 02215 USA.

mutations were recently found to be an important mechanism of endocrine resistance in ER-positive (ER + ) metastatic breast cancer. To determine the clinicopathological features driving the emergence of the mutations we studied plasma cfDNA and detailed clinical data collected from patients with metastatic breast cancer. Droplet Digital PCR was performed for the detection of the most common mutations and mutations. Among the patients with ER + /HER2- disease, mutations were detected in 30% of the patients. There were no associations between the pathological features of the primary disease or time to distant recurrence and the emergence of mutations in metastatic disease. The prevalence of the mutations was significantly associated with prior treatment with an aromatase inhibitor in the adjuvant or metastatic setting. The prevalence of the mutations was also positively associated with prior fulvestrant treatment. Conversely, the prevalence of mutations was lower after treatment with a CDK4/6 inhibitor. There were no significant associations between specific systemic treatments and the prevalence of mutations. These results support the evolution of the mutations under the selective pressure of treatment with aromatase inhibitors in the adjuvant and metastatic settings and have important implications in the optimization of adjuvant and metastatic treatment in ER + breast cancer.
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http://dx.doi.org/10.1038/s41523-018-0075-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072793PMC
August 2018

Treating Second Breast Events After Breast-Conserving Surgery for Ductal Carcinoma in Situ.

J Natl Compr Canc Netw 2018 04;16(4):387-394

Because of screening mammography, the number of ductal carcinoma in situ (DCIS) survivors has increased dramatically. DCIS survivors may face excess risk of second breast events (SBEs). However, little is known about SBE treatment or its relationship to initial DCIS care. Among a prospective cohort of women who underwent breast-conserving surgery (BCS) for DCIS from 1997 to 2008 at institutions participating in the NCCN Outcomes Database, we identified SBEs, described patterns of care for SBEs, and examined the association between DCIS treatment choice and SBE care. Using multivariable regression, we identified features associated with use of mastectomy, radiation therapy (RT), or antiestrogen therapy (AET) for SBEs. Of 2,939 women who underwent BCS for DCIS, 83% received RT and 40% received AET. During the median follow-up of 4.2 years, 200 women (6.8%) developed an SBE (55% ipsilateral, 45% invasive). SBEs occurred in 6% of women who underwent RT for their initial DCIS versus 11% who did not. Local treatment for these events included BCS (10%), BCS/RT (30%), mastectomy (53%), or none (6%); only 28% of patients received AET. Independent predictors of RT or mastectomy for SBEs included younger age, shorter time to SBE diagnosis, and RT or AET for the initial DCIS. A sizable proportion of patients with SBEs were treated with mastectomy, most especially those who previously received RT for their initial DCIS and those who developed an ipsilateral SBE. Despite the occurrence of an SBE, relatively few patients received AET. Future studies should investigate optimal treatment approaches for SBEs, including the benefit of mastectomy versus lumpectomy for an ipsilateral SBE and the benefit of AET for a hormone-receptor-positive SBE contingent on AET use for the initial DCIS diagnosis.
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http://dx.doi.org/10.6004/jnccn.2018.7003DOI Listing
April 2018

Association of Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations With Survival in Metastatic Triple-Negative Breast Cancer.

J Clin Oncol 2018 02 3;36(6):543-553. Epub 2018 Jan 3.

Daniel G. Stover, Ohio State University Comprehensive Cancer Center, Columbus, OH; Heather A. Parsons, Gavin Ha, William T. Barry, Hao Guo, Atish D. Choudhury, Melissa E. Hughes, Deborah A. Dillon, Ann H. Partridge, Nikhil Wagle, Ian E. Krop, Todd R. Golub, Eric P. Winer, Sara M. Tolaney, and Nancy U. Lin, Dana-Farber Cancer Institute; Gad Getz, Massachusetts General Hospital, Boston; Gavin Ha, Samuel S. Freeman, Atish D. Choudhury, Gregory Gydush, Sarah C. Reed, Justin Rhoades, Denisse Rotem, Nikhil Wagle, Gad Getz, Todd R. Golub, and Viktor A. Adalsteinsson, Broad Institute of Harvard and Massachusetts Institute of Technology; and J. Christopher Love, Massachusetts Institute of Technology, Cambridge, MA.

Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.
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http://dx.doi.org/10.1200/JCO.2017.76.0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815405PMC
February 2018

Clinical risk score to predict likelihood of recurrence after ductal carcinoma in situ treated with breast-conserving surgery.

Breast Cancer Res Treat 2018 02 28;167(3):751-759. Epub 2017 Oct 28.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Purpose: A majority of women with ductal carcinoma in situ (DCIS) receive breast-conserving surgery (BCS) but then face a risk of ipsilateral breast tumor recurrence (IBTR) which can be either recurrence of DCIS or invasive breast cancer. We developed a score to provide individualized information about IBTR risk to guide treatment decisions.

Methods: Data from 2762 patients treated with BCS for DCIS at centers within the National Comprehensive Cancer Network (NCCN) were used to identify statistically significant non-treatment-related predictors for 5-year IBTR. Factors most associated with IBTR were estrogen-receptor status of the DCIS, presence of comedo necrosis, and patient age at diagnosis. These three parameters were used to create a point-based risk score. Discrimination of this score was assessed in a separate DCIS population of 301 women (100 with IBTR and 200 without) from Kaiser Permanente Northern California (KPNC).

Results: Using NCCN data, the 5-year likelihood of IBTR without adjuvant therapy was 9% (95% CI 5-12%), 23% (95% CI 13-32%), and 51% (95% CI 26-75%) in the low, intermediate, and high-risk groups, respectively. Addition of the risk score to a model including only treatment improved the C-statistic from 0.69 to 0.74 (improvement of 0.05). Cross-validation of the score resulted in a C-statistic of 0.76. The score had a c-statistic of 0.67 using the KPNC data, revealing that it discriminated well.

Conclusions: This simple, no-cost risk score may be used by patients and physicians to facilitate preference-based decision-making about DCIS management informed by a more accurate understanding of risks.
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http://dx.doi.org/10.1007/s10549-017-4553-5DOI Listing
February 2018

Variation in the use of granulocyte-colony stimulating factor for dose dense paclitaxel: A single institution retrospective study.

Breast 2016 Dec 6;30:136-140. Epub 2016 Oct 6.

Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address:

Introduction: The necessity of using granulocyte-colony stimulating factor (G-CSF) during dose-dense (DD) paclitaxel (T) after doxorubicin and cyclophosphamide (AC) is unclear.

Methods: This was a retrospective cohort study including patients with stage I-III breast cancer treated at Dana-Farber Cancer Institute with adjuvant DD-ACT between January 2011 and December 2013. Descriptive analyses evaluating patterns of G-CSF utilization during T were performed.

Results: Overall, 156 patients were treated with DD-ACT by 26 providers. The majority of patients (135, 87%) received at least one dose of G-CSF during T (group 1), 17% of these patients received it in only one cycle and 48% received it in all four cycles. Reasons for omitting G-CSF included high baseline absolute neutrophil count and pain. Twenty-one (13%) patients did not receive any G-CSF during T (group 2). Respectively, 94% and 90% of patients completed the treatment in groups 1 and 2. There were no cases of treatment cessation due to neutropenia. Six percent of patients in group 1 had at least one treatment delay. There were no treatment delays reported in group 2. Variation in the use of G-CSF by provider and by patient was found, with 11 providers choosing not to use G-CSF in at least one patient.

Conclusions: We identified substantial variation in the use of G-CSF within the practice. However, omission of G-CSF was not associated with treatment delays or adverse events. Prospective studies are warranted to formally test whether routine G-CSF is necessary during dose-dense T therapy.
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http://dx.doi.org/10.1016/j.breast.2016.09.013DOI Listing
December 2016

Subtype-Dependent Relationship Between Young Age at Diagnosis and Breast Cancer Survival.

J Clin Oncol 2016 09 1;34(27):3308-14. Epub 2016 Aug 1.

Ann H. Partridge, Melissa E. Hughes, Erica T. Warner, Eric P. Winer, Jane C. Weeks, and Rulla M. Tamimi, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Erica T. Warner, Harvard T.H. Chan School of Public Health, Boston, MA; Rebecca A. Ottesen and Joyce C. Niland, City of Hope Comprehensive Cancer Center, Duarte; and Douglas W. Blayney, Stanford Cancer Institute, Palo Alto, CA; Yu-Ning Wong, Fox Chase Cancer Center, Philadelphia, PA; Stephen B. Edge, Baptist Cancer Center, Memphis, TN; and Richard L. Theriault, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Young women are at increased risk for developing more aggressive subtypes of breast cancer. Although previous studies have shown a higher risk of breast cancer recurrence and death among young women with early-stage breast cancer, they have not adequately addressed the role of tumor subtype in outcomes.

Methods: We examined data from women with newly diagnosed stage I to III breast cancer presenting to one of eight National Comprehensive Cancer Network centers between January 2000 and December 2007. Multivariable Cox proportional hazards models were used to assess the relationship between age and breast cancer-specific survival.

Results: A total of 17,575 women with stage I to III breast cancer were eligible for analysis, among whom 1,916 were ≤ 40 years of age at diagnosis. Median follow-up time was 6.4 years. In a multivariable Cox proportional hazards model controlling for sociodemographic, disease, and treatment characteristics, women ≤ 40 years of age at diagnosis had greater breast cancer mortality (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.7). In stratified analyses, age ≤ 40 years was associated with statistically significant increases in risk of breast cancer death among women with luminal A (HR, 2.1; 95% CI, 1.4 to 3.2) and luminal B (HR 1.4; 95% CI, 1.1 to 1.9) tumors, with borderline significance among women with triple-negative tumors (HR, 1.4; 95% CI, 1.0 to 1.8) but not among those with human epidermal growth factor receptor 2 subtypes (HR, 1.2; 95% CI, 0.8 to 1.9). In an additional model controlling for detection method, young age was associated with significantly increased risk of breast cancer death only among women with luminal A tumors.

Conclusion: The effect of age on survival of women with early breast cancer seems to vary by breast cancer subtype. Young age seems to be particularly prognostic in women with luminal breast cancers.
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http://dx.doi.org/10.1200/JCO.2015.65.8013DOI Listing
September 2016

Trends in the use of mastectomy in women with small node-negative breast cancer treated at US academic centers.

Breast Cancer Res Treat 2016 Feb 11;155(3):569-78. Epub 2016 Feb 11.

Dana-Farber Cancer Institute, Boston, MA, USA.

Breast-conserving surgery (BCS) provides equivalent survival outcomes to unilateral mastectomy. There is no survival advantage to bilateral mastectomy in average risk breast cancer. Among a cohort of breast cancer patients expected to be candidates for BCS, we examined choice of surgery and factors associated with it. A prospective cohort study of unilateral clinical Stage I breast cancer patients treated at National Comprehensive Cancer Network centers from 2000 to 2009 was performed. The proportion of patients who initially underwent mastectomy versus BCS and time to definitive surgery and chemotherapy were examined. Of 10,249 patients, 23 % underwent mastectomy as an initial surgery. No decline in the use of mastectomy as initial surgery was found. There was significant institutional variation, with rates of initial mastectomy ranging from 14 to 30 % (adjusted odds ratio: 0.42-1.38). Tumor characteristics were associated with surgical option, but with small absolute differences. Of those who received initial mastectomy, 22 % had bilateral mastectomy, with an increase over time (2000:13 % vs. 2009:30 %) and substantial institutional variation (11-34 %). Women treated with initial mastectomy had longer median times from diagnosis to complete definitive surgery (6 vs. 4 weeks) and to start of adjuvant chemotherapy (12 vs. 11 weeks). Among Stage I breast cancer, the overall use of mastectomy did not change significantly over 10 years; however, an increasing proportion of women with unilateral cancer had bilateral mastectomy, and there was wide variation in type of surgery by institution. Further studies to assess reasons for the observed wide variation are warranted.
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http://dx.doi.org/10.1007/s10549-016-3707-1DOI Listing
February 2016

Biological Subtype Predicts Risk of Locoregional Recurrence After Mastectomy and Impact of Postmastectomy Radiation in a Large National Database.

Int J Radiat Oncol Biol Phys 2015 Nov 11;93(3):622-30. Epub 2015 Jul 11.

Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts.

Purpose: To evaluate locoregional recurrence (LRR) after mastectomy and impact of postmastectomy radiation (PMRT) by breast cancer subtype.

Methods And Materials: Between 2000 and 2009, 5673 patients with stage I to III breast carcinoma underwent mastectomy and nodal evaluation; 30% received PMRT. Isolated LRR (iLRR) and LRR were compared across groups defined by biological subtype and receipt of trastuzumab: luminal A (estrogen [ER]/progesterone [PR]+, HER2-, low/intermediate grade), luminal B (ER/PR+, HER2-, high grade), HER2 with trastuzumab, HER2 without trastuzumab, and triple negative (TN; ER-, PR-, HER2-). LRR hazard ratios (HR) were estimated with multivariable Fine and Gray models. The effect of PMRT on LRR was evaluated with Fine and Gray models stratified by propensity for PMRT.

Results: With a median follow-up time of 50.1 months, there were 19 iLRR and 109 LRR events. HER2 patients with trastuzumab had no iLRR and only a single LRR. Compared with luminal A patients, TN patients had significantly greater adjusted risk of iLRR (HR 14.10; 95% CI 2.97%-66.90%), with a similar trend among luminal B (HR 4.94; 95% CI 0.94%-25.82%) and HER2 patients without trastuzumab (HR 4.41; 95% CI 0.61%-32.11%). Although PMRT reduced LRR, the effect of PMRT varied by subgroup, with the greatest and smallest effects seen among luminal A (HR 0.17; 95% CI 0.05%-0.62%) and TN patients (HR 0.59; 95% CI 0.25%-1.35%), respectively.

Conclusions: TN patients had the highest risk of LRR and the least benefit from PMRT; these patients may benefit from alternative treatment strategies. In contrast, in the era of HER2-directed therapy, the role of local therapy may need to be reassessed among HER2 patients.
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http://dx.doi.org/10.1016/j.ijrobp.2015.07.006DOI Listing
November 2015

Racial and Ethnic Differences in Breast Cancer Survival: Mediating Effect of Tumor Characteristics and Sociodemographic and Treatment Factors.

J Clin Oncol 2015 Jul 11;33(20):2254-61. Epub 2015 May 11.

Erica T. Warner and Rulla M. Tamimi, Harvard School of Public Health; Erica T. Warner, Rulla M. Tamimi, Melissa E. Hughes, Eric P. Winer, Jane C. Weeks, and Ann H. Partridge, Brigham and Women's Hospital; Melissa E. Hughes, Eric P. Winer, Jane C. Weeks, and Ann H. Partridge, Dana-Farber Cancer Institute, Boston, MA; Rebecca A. Ottesen and Joyce C. Niland, City of Hope Comprehensive Cancer Center, Duarte; Douglas W. Blayney, Stanford University Cancer Center, Palo Alto, CA; Yu-Ning Wong, Fox Chase Cancer Center, Philadelphia, PA; Stephen B. Edge, Baptist Cancer Center, Memphis, TN; and Richard L. Theriault, University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: To evaluate the relationship between race/ethnicity and breast cancer-specific survival according to subtype and explore mediating factors.

Patients And Methods: Participants were women presenting with stage I to III breast cancer between January 2000 and December 2007 at National Comprehensive Cancer Network centers with survival follow-up through December 2009. Cox proportional hazards regression was used to compare breast cancer-specific survival among Asians (n = 533), Hispanics (n = 1,122), and blacks (n = 1,345) with that among whites (n = 14,268), overall and stratified by subtype (luminal A like, luminal B like, human epidermal growth factor receptor 2 type, and triple negative). Model estimates were used to derive mediation proportion and 95% CI for selected risk factors.

Results: In multivariable adjusted models, overall, blacks had 21% higher risk of breast cancer-specific death (hazard ratio [HR], 1.21; 95% CI, 1.00 to 1.45). For estrogen receptor-positive tumors, black and white survival differences were greatest within 2 years of diagnosis (years 0 to 2: HR, 2.65; 95% CI, 1.34 to 5.24; year 2 to end of follow-up: HR, 1.50; 95% CI, 1.12 to 2.00). Blacks were 76% and 56% more likely to die as a result of luminal A-like and luminal B-like tumors, respectively. No disparities were observed for triple-negative or human epidermal growth factor receptor 2-type tumors. Asians and Hispanics were less likely to die as a result of breast cancer compared with whites (Asians: HR, 0.56; 95% CI, 0.37 to 0.85; Hispanics: HR, 0.74; 95% CI, 0.58 to 0.95). For blacks, tumor characteristics and stage at diagnosis were significant disparity mediators. Body mass index was an important mediator for blacks and Asians.

Conclusion: Racial disparities in breast cancer survival vary by tumor subtype. Interventions are needed to reduce disparities, particularly in the first 2 years after diagnosis among black women with estrogen receptor-positive tumors.
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http://dx.doi.org/10.1200/JCO.2014.57.1349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486344PMC
July 2015

Variation in type of adjuvant chemotherapy received among patients with stage I breast cancer: A multi-institutional study.

Cancer 2015 Jun 10;121(12):1937-48. Epub 2015 Mar 10.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Among patients with stage I breast cancer, there is significant uncertainty concerning the optimal threshold at which to consider chemotherapy, and when considered, there is controversy regarding whether to consider non-intensive versus intensive regimens. The authors examined the types and costs of adjuvant chemotherapy received among patients with stage I breast cancer.

Methods: The current study was a prospective cohort study including patients with stage I breast cancer who were treated at a National Comprehensive Cancer Network center from 2000 through 2009. Stage was defined according to the version of the American Joint Committee on Cancer Staging Manual applicable at the time of diagnosis. Stratifying by human epidermal growth factor receptor 2 (HER2), the authors examined the percentage of patients receiving intensive versus non-intensive chemotherapy regimens and the factors associated with type of chemotherapy administered using multivariable logistic regression. Costs of the most common regimens were estimated.

Results: Of 8907 patients, 33% received adjuvant chemotherapy. Among those individuals, there was an increase in the use of intensive chemotherapy within the last decade, from 31% in 2000 through 2005 to 63% in 2008 through 2009 (including an increase in the use of the combination of docetaxel, carboplatin, and trastuzumab) among patients with HER2-positive disease and from 15% in 2000 through 2005 to 41% in 2008 through 2009 among patients with HER2-negative disease (32% of patients with hormone receptor-positive and 59% of patients with triple-negative disease). Among patients treated with non-intensive regimens, there was an increase in the use of the combination of docetaxel and cyclophosphamide noted, with a decrease in the use of the doxorubicin and cyclophosphamide combination. The choice of regimen varied significantly by institution. The major drivers of cost variation were the incorporation of biologics (eg, trastuzumab) and growth factors, with significant variation even within non-intensive and intensive regimens.

Conclusions: Over time, there was an increase in use of intensive regimens among Stage I breast cancer, with striking institutional and cost variations.
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http://dx.doi.org/10.1002/cncr.29310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457605PMC
June 2015

Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience.

J Clin Oncol 2015 Feb 22;33(4):340-8. Epub 2014 Dec 22.

Antonio C. Wolff, Amanda L. Blackford, Kala Visvanathan, Terry S. Langbaum, and Judith E. Karp, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Hope S. Rugo, University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA; Beverly Moy, Massachusetts General Hospital Cancer Center; Melissa E. Hughes and Jane C. Weeks, Dana-Farber Cancer Institute, Boston, MA; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Keith Stockerl-Goldstein, Siteman Cancer Center at Washington University School of Medicine, St Louis, MO; Leigh Neumayer, Huntsman Cancer Center at University of Utah School of Medicine, Salt Lake City, UT; and Richard L. Theriault, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Outcomes for early-stage breast cancer have improved. First-generation adjuvant chemotherapy trials reported a 0.27% 8-year cumulative incidence of myelodysplastic syndrome/acute myelogenous leukemia. Incomplete ascertainment and follow-up may have underestimated subsequent risk of treatment-associated marrow neoplasm (MN).

Patients And Methods: We examined the MN frequency in 20,063 patients with stage I to III breast cancer treated at US academic centers between 1998 and 2007. Time-to-event analyses were censored at first date of new cancer event, last contact date, or death and considered competing risks. Cumulative incidence, hazard ratios (HRs), and comparisons with Surveillance, Epidemiology, and End Results estimates were obtained. Marrow cytogenetics data were reviewed.

Results: Fifty patients developed MN (myeloid, n = 42; lymphoid, n = 8) after breast cancer (median follow-up, 5.1 years). Patients who developed MN had similar breast cancer stage distribution, race, and chemotherapy exposure but were older compared with patients who did not develop MN (median age, 59.1 v 53.9 years, respectively; P = .03). Two thirds of patients had complex MN cytogenetics. Risk of MN was significantly increased after surgery plus chemotherapy (HR, 6.8; 95% CI, 1.3 to 36.1) or after all modalities (surgery, chemotherapy, and radiation; HR, 7.6; 95% CI, 1.6 to 35.8), compared with no treatment with chemotherapy. MN rates per 1,000 person-years were 0.16 (surgery), 0.43 (plus radiation), 0.46 (plus chemotherapy), and 0.54 (all three modalities). Cumulative incidence of MN doubled between years 5 and 10 (0.24% to 0.48%); 9% of patients were alive at 10 years.

Conclusion: In this large early-stage breast cancer cohort, MN risk after radiation and/or adjuvant chemotherapy was low but higher than previously described. Risk continued to increase beyond 5 years. Individual risk of MN must be balanced against the absolute survival benefit of adjuvant chemotherapy.
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http://dx.doi.org/10.1200/JCO.2013.54.6119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302215PMC
February 2015

Impact of guideline changes on use or omission of radiation in the elderly with early breast cancer: practice patterns at National Comprehensive Cancer Network institutions.

J Am Coll Surg 2014 Oct 6;219(4):796-802. Epub 2014 Jun 6.

Baptist Cancer Center, Memphis, TN; Vanderbilt University School of Medicine, Nashville, TN.

Background: Breast radiation therapy (RT) is a care standard after breast-conservation surgery that improves local control and survival in women. In 2004, a phase III trial demonstrated radiation after breast-conservation surgery provided no survival and limited local control benefit to women aged 70 years and older with stage I, estrogen receptor-positive cancers who receive endocrine therapy. This led to breast-conservation surgery and endocrine therapy alone being incorporated as a category I option in the National Comprehensive Cancer Network (NCCN) Guidelines for older women in 2004. We examined factors associated with change in radiation use in elderly patients at 13 NCCN centers.

Study Design: We identified women treated at NCCN centers meeting age and stage criteria during 2000 to 2009. Factors considered a priori potentially associated with RT use were evaluated in univariate and multivariable models, including year of diagnosis, tumor and patient characteristics, axillary surgery, and treating institution. Date of diagnosis was classified as 2000 to 2004 vs 2005 to 2009, reflecting when guidelines changed.

Results: Among 1,292 eligible cases, 78% received RT. In multivariable analysis, diagnosis after 2004 (p = 0.0003), older age (p < 0.0001), higher comorbidity score (p = 0.0006), smaller tumors (p = 0.0146), and omission of axillary surgery (p < 0.0001) predicted RT omission. Ninety-four percent of women aged 70 to 74 years received RT in 2000, compared with 88% in 2009. For the same times and age 80 years and older, RT use was 80% vs 41%. Finally, RT use was associated with treating institution (p < 0.0001).

Conclusions: After guideline changes for RT use in older women, NCCN centers demonstrated wide variation in implementing change. This suggests other factors are also influencing guideline uptake.
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http://dx.doi.org/10.1016/j.jamcollsurg.2014.05.013DOI Listing
October 2014

Inflammatory breast cancer management in the national comprehensive cancer network: the disease, recurrence pattern, and outcome.

Clin Breast Cancer 2015 Feb 23;15(1):1-7. Epub 2014 Jun 23.

Fox Chase Cancer Center, Philadelphia, PA.

Background: Inflammatory breast cancer (IBC) is an uncommon clinicopathologic entity characterized by rapid progression and aggressive behavior. We used the National Comprehensive Cancer Network (NCCN) Outcomes Database to characterize recurrence patterns and outcomes.

Methods: Patients with newly diagnosed IBC treated between 1999 and 2009 at 12 NCCN institutions were identified, and baseline characteristics were obtained. Patients had multimodality therapy if they received 2 of 3 treatments: surgery, perioperative (neoadjuvant or adjuvant) chemotherapy, or perioperative radiation. The first site of recurrence/metastatic diagnosis was identified. Overall survival was calculated on the basis of stage at diagnosis and receipt of multimodality therapy.

Results: We identified 673 patients, of whom 195 (29%) had metastatic disease at presentation. Median follow-up was 29 months. Of patients in stage III, 82% received > 1 treatment modality. Among 203 patients in stage III with recurrence, the most frequent sites of first recurrence were bone (28%), central nervous system (CNS), lung, and liver (all 21%). Human epidermal growth factor receptor 2 positive and triple negative subtypes had higher rates of CNS recurrence (P = .001). Median survival was 66 months (95% confidence interval [CI], 54-107) for stage III and 26 months (95% CI, 22-33) for stage IV. Among 82% of patients in stage III receiving multimodality therapy, the median survival was 107 months (95% CI, 71 to not reached).

Conclusions: This large, retrospective, multi-institutional study confirms the aggressive clinical features, unique recurrence patterns, and adverse prognosis of IBC. The high rate of CNS recurrence among high-risk subtypes, despite the inflammatory nature of the breast cancer, suggests that new strategies are needed for earlier detection or prevention of brain metastases to improve long-term prognosis.
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http://dx.doi.org/10.1016/j.clbc.2014.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422394PMC
February 2015

Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: a multi-institutional study.

J Clin Oncol 2014 Jul 2;32(20):2142-50. Epub 2014 Jun 2.

Ines Vaz-Luis, Melissa E. Hughes, Harold J. Burstein, Jane C. Weeks, Eric P. Winer, and Nancy U. Lin, Dana-Farber Cancer Institute; Beverly Moy, Massachusetts General Hospital, Boston, MA; Ines Vaz-Luis, Instituto de Medicina Molecular, Lisbon, Portugal; Rebecca A. Ottesen and Rizvan Mamet, City of Hope, Duarte; Hope S. Rugo, University of California, San Francisco, San Francisco, CA; Stephen B. Edge, Roswell Park Cancer Institute, Buffalo, NY; Stephen B. Edge, Baptist Cancer Center, Memphis, TN; and Ana M. Gonzalez-Angulo and Richard L. Theriault, University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Treatment decisions for patients with T1a,bN0M0 breast cancer are challenging. We studied the time trends in use of adjuvant chemotherapy and survival outcomes among these patients.

Patients And Methods: This was a prospective cohort study within the National Comprehensive Cancer Network Database that included 4,113 women with T1a,bN0M0 breast cancer treated between 2000 and 2009. Tumors were grouped by size (T1a, T1b), biologic subtype defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, and receipt of chemotherapy with or without trastuzumab.

Results: Median follow-up time was 5.5 years. Eight percent of patients with HR-positive/HER2-negative tumors were treated with chemotherapy. Fifty-two percent of those with HER2-positive or HR-negative/HER2-negative breast cancers received chemotherapy, with an increase over the last decade. Survival outcomes diverged by subtype and size, but the 5-year distant relapse-free survival (DRFS) did not exceed 10% in any subgroup. The 5-year DRFS for patients with T1a tumors untreated with chemotherapy ranged from 93% to 98% (n = 49 to 972), and for patients with T1b tumors, it ranged from 90% to 96% (n = 17 to 2,005). Patients with HR-positive/HER2-negative disease had the best DRFS estimates, and patients with HR-negative/HER2-negative tumors had the lowest. In this observational, nonrandomized cohort study, the 5-year DRFS for treated patients with T1a tumors was 100% for all subgroups (n = 12 to 33), and for patients with T1b tumors, it ranged from 94% to 96% (n = 88 to 241).

Conclusion: Women with T1a,b tumors have an excellent prognosis without chemotherapy. Size and tumor subtype may identify patients in whom the rate of recurrence justifies consideration of chemotherapy. These patients represent an optimal group for evaluating less toxic adjuvant regimens to maintain efficacy while minimizing short- and long-term risks.
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http://dx.doi.org/10.1200/JCO.2013.53.1608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076026PMC
July 2014

Characterization and treatment of local recurrence following breast conservation for ductal carcinoma in situ.

Ann Surg Oncol 2014 Nov 24;21(12):3766-73. Epub 2014 May 24.

Wisconsin Surgical Outcomes Research (WiSOR) Program, Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, WI, USA,

Purpose: The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences.

Methods: We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) (N = 182).

Results: Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09).

Conclusion: We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered.
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http://dx.doi.org/10.1245/s10434-014-3802-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539255PMC
November 2014

Time to diagnosis and breast cancer stage by race/ethnicity.

Breast Cancer Res Treat 2012 Dec 26;136(3):813-21. Epub 2012 Oct 26.

Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115, USA.

We examined differences in time to diagnosis by race/ethnicity, the relationship between time to diagnosis and stage, and the extent to which it explains differences in stage at diagnosis across racial/ethnic groups. Our analytic sample includes 21,427 non-Hispanic White (White), Hispanic, non-Hispanic Black (Black) and non-Hispanic Asian/Pacific Islander (Asian) women diagnosed with stage I to IV breast cancer between January 1, 2000 and December 31, 2007 at one of eight National Comprehensive Cancer Network centers. We measured time from initial abnormal mammogram or symptom to breast cancer diagnosis. Stage was classified using AJCC criteria. Initial sign of breast cancer modified the association between race/ethnicity and time to diagnosis. Among symptomatic women, median time to diagnosis ranged from 36 days among Whites to 53.6 for Blacks. Among women with abnormal mammograms, median time to diagnosis ranged from 21 days among Whites to 29 for Blacks. Blacks had the highest proportion (26 %) of Stage III or IV tumors. After accounting for time to diagnosis, the observed increased risk of stage III/IV breast cancer was reduced from 40 to 28 % among Hispanics and from 113 to 100 % among Blacks, but estimates remained statistically significant. We were unable to fully account for the higher proportion of late-stage tumors among Blacks. Blacks and Hispanics experienced longer time to diagnosis than Whites, and Blacks were more likely to be diagnosed with late-stage tumors. Longer time to diagnosis did not fully explain differences in stage between racial/ethnicity groups.
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http://dx.doi.org/10.1007/s10549-012-2304-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513497PMC
December 2012

Impact of hormone receptor status on patterns of recurrence and clinical outcomes among patients with human epidermal growth factor-2-positive breast cancer in the National Comprehensive Cancer Network: a prospective cohort study.

Breast Cancer Res 2012 Oct 1;14(5):R129. Epub 2012 Oct 1.

Introduction: In gene expression experiments, hormone receptor (HR)-positive/human epidermal growth factor-2 (HER2)-positive tumors generally cluster within the luminal B subset; whereas HR-negative/HER2-positive tumors reside in the HER2-enriched subset. We investigated whether the clinical behavior of HER2-positive tumors differs by HR status.

Methods: We evaluated 3,394 patients who presented to National Comprehensive Cancer Network (NCCN) centers with stage I to III HER2-positive breast cancer between 2000 and 2007. Tumors were grouped as HR-positive/HER2-positive (HR+/HER2+) or HR-negative/HER2-positive (HR-/HER2+). Chi-square, logistic regression and Cox hazard proportional regression were used to compare groups.

Results: Median follow-up was four years. Patients with HR-/HER2+ tumors (n = 1,379, 41% of total) were more likely than those with HR+/HER-2+ disease (n = 2,015, 59% of total) to present with high histologic grade and higher stages (P <0.001). Recurrences were recorded for 458 patients. HR-/HER2+ patients were less likely to experience first recurrence in bone (univariate Odds Ratio (OR) = 0.53, 95% Confidence Interval (CI): 0.34 to 0.82, P = 0.005) and more likely to recur in brain (univariate OR = 1.75, 95% CI: 1.05 to 2.93, P = 0.033). A lower risk of recurrence in bone persisted after adjusting for age, stage and adjuvant trastuzumab therapy (OR = 0.53, 95% CI: 0.34 to 0.83, P = 0.005) and when first and subsequent sites of recurrence were both considered (multivariable OR = 0.55, 95% CI: 0.37 to 0.80, P = 0.002).

Conclusions: Presenting features, patterns of recurrence and survival of HER2-positive breast cancer differed by HR status. These differences should be further explored and integrated in the design of clinical trials.
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http://dx.doi.org/10.1186/bcr3324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053106PMC
October 2012

Use of adjuvant trastuzumab in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer by race/ethnicity and education within the National Comprehensive Cancer Network.

Cancer 2013 Feb 25;119(4):839-46. Epub 2012 Sep 25.

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.

Background: Trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly efficacious yet costly and time-intensive, and few data are available about its use. The authors of this report examined receipt and completion of adjuvant trastuzumab by race/ethnicity and education for women with HER2-positive disease.

Methods: The National Comprehensive Cancer Network Breast Cancer Outcomes Database was used to identify 1109 women who were diagnosed with stage I through III, HER2-positive breast cancer during September 2005 through December 2008 and were followed for ≥1 year. The authors used multivariable logistic regression to assess the association of race/ethnicity and education with the receipt of trastuzumab and, among those women who initiated trastuzumab, with the completion of > 270 days of therapy.

Results: The cohort was 75% white, 8% black, and 9% Hispanic; and 20% of women had attained a high school degree or less. Most women (83%) received trastuzumab, and no significant differences were observed according to race/ethnicity or socioeconomic status. Among the women who initiated trastuzumab, 73% of black women versus 87% of white women (P = .007) and 70% of women with less than a high school education versus 90% of women with a college degree completed > 270 days of therapy (P = .006). In adjusted analyses, black women (vs white women) and women without a high school degree (vs those with a college degree) had lower odds of completing therapy (black women: odds ratio, 0.45; 95% confidence interval, 0.27-074; white women: odds ratio, 0.27, 95% confidence interval, 0.14-0.51).

Conclusions: Differences in completing trastuzumab therapy were observed according to race and educational attainment among women who received treatment at National Comprehensive Cancer Network centers. Efforts to assure the appropriate use of trastuzumab and to understand treatment barriers are needed and may lead to improved outcomes. The authors report differences in the rate at which patients complete treatment with trastuzumab according to race and education among women who receive treatment at National Comprehensive Cancer Network centers. Efforts to assure the appropriate use of trastuzumab and to understand treatment barriers are needed and may lead to improved outcomes.
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http://dx.doi.org/10.1002/cncr.27831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565006PMC
February 2013

Pathologic characteristics of second breast cancers after breast conservation for ductal carcinoma in situ.

Cancer 2012 Dec 6;118(24):6022-30. Epub 2012 Jun 6.

Harvard Radiation Oncology Program, Harvard Medical School, Boston, Massachusetts, USA.

Background: The number of women diagnosed with ductal carcinoma in situ (DCIS) is increasing. Although many eventually develop a second breast cancer (SBC), little is known about the characteristics of SBCs. The authors described the characteristics of SBC and examined associations between the pathologic features of SBC and index DCIS cases.

Methods: Women were identified in the National Comprehensive Cancer Network Outcomes Database who were diagnosed with DCIS from 1997 to 2008 and underwent lumpectomy and who subsequently developed SBC (including DCIS or invasive disease that occurred in the ipsilateral or contralateral breast). The Fisher exact test and the Spearman test were used to examine associations between the pathologic characteristics of SBC and index DCIS cases.

Results: Among 2636 women who underwent lumpectomy for DCIS, 150 (5.7%) experienced an SBC after a median of 55.5 months of follow-up. Of these 150 women, 105 (70%) received adjuvant radiotherapy, and 50 (33.3%) received tamoxifen for their index DCIS. SBCs were ipsilateral in 54.7% of women and invasive in 50.7% of women. Among the index DCIS cases, 60.6% were estrogen receptor (ER)-positive, and 54% were high grade, whereas 77.5% of SBCs were ER-positive, and 48.2% were high grade. Tumor grade (P = .003) and ER status (P = .02) were associated significantly between index DCIS and SBC, whereas tumor size was not (P = .87).

Conclusions: After breast conservation for DCIS, SBC in either breast exhibited pathologic characteristics similar to the index DCIS, suggesting that women with DCIS may be at risk for developing subsequent breast cancers of a similar phenotype.
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http://dx.doi.org/10.1002/cncr.27691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496800PMC
December 2012

Adoption of gene expression profile testing and association with use of chemotherapy among women with breast cancer.

J Clin Oncol 2012 Jun 14;30(18):2218-26. Epub 2012 May 14.

Center for Outcomes and Policy Research, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.

Purpose: Gene expression profile (GEP) testing is a relatively new technology that offers the potential of personalized medicine to patients, yet little is known about its adoption into routine practice. One of the first commercially available GEP tests, a 21-gene profile, was developed to estimate the benefit of adjuvant chemotherapy for hormone receptor-positive breast cancer (HR-positive BC).

Patients And Methods: By using a prospective registry data set outlining the routine care provided to women diagnosed from 2006 to 2008 with HR-positive BC at 17 comprehensive and community-based cancer centers, we assessed GEP test adoption and the association between testing and chemotherapy use.

Results: Of 7,375 women, 20.4% had GEP testing and 50.2% received chemotherapy. Over time, testing increased (14.7% in 2006 to 27.5% in 2008; P < .01) and use of chemotherapy decreased (53.9% in 2006 to 47.0% in 2008; P < .01). Characteristics independently associated with lower odds of testing included African American versus white race (odds ratio [OR], 0.70; 95% CI, 0.54 to 0.92) and high school or less versus more than high school education (OR, 0.63; 95% CI, 0.52 to 0.76). Overall, testing was associated with lower odds of chemotherapy use (OR, 0.70; 95% CI, 0.62 to 0.80). Stratified analyses demonstrated that for small, node-negative cancers, testing was associated with higher odds of chemotherapy use (OR, 11.13; 95% CI, 5.39 to 22.99), whereas for node-positive and large node-negative cancers, testing was associated with lower odds of chemotherapy use (OR, 0.11; 95% CI, 0.07 to 0.17).

Conclusion: There has been a progressive increase in use of this GEP test and an associated shift in the characteristics of and overall reduction in the proportion of women with HR-positive BC receiving adjuvant chemotherapy.
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http://dx.doi.org/10.1200/JCO.2011.38.5740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397718PMC
June 2012