Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Impact of axillary surgery on outcome of clinically node positive breast cancer treated with neoadjuvant chemotherapy.

PURPOSE: Axillary Lymph Node Dissection (ALND) is recommended for breast cancer patients who present with clinically node positive disease (cN1) especially if they have residual nodal disease (ypN+) following neoadjuvant therapy (NAT). It is unknown whether axillary dissection improves outcome for these patients. METHODS: A prospectively maintained database was used to identify all patients who were diagnosed with cTis-T4N1M0 breast cancer treated with NAT. RESULTS: In our study, of 292 cN1 breast cancer patients who received NAT, we compared ALND with targeted axillary surgery (TAS) in ypN+ patients. ALND was performed in 75% of the ypN+ subgroup, while 25% underwent TAS. Axillary recurrence occurred in four ALND patients, but no recurrence was observed in the TAS group (p = 0.21). Five-year axillary recurrence-free survival was 100% for TAS and 90% for ALND (p = 0.21). Overall survival at five years was 97% for TAS and 85% for ALND (p = 0.39). Disease-free survival rates at five years were 51% for TAS and 61% for ALND (p = 0.9). Clinicopathological variables were similar between the groups, although some differences were noted. ALND patients had smaller clinical tumor size, larger pathological tumor size, more lymph nodes retrieved, larger tumor deposits, higher rates of extranodal extension, and greater prevalence of macrometastatic nodal disease. Tumor subtype and size of lymph node tumor deposit independently predicted survival. CONCLUSION: Axillary recurrence is infrequent in cN1 patients treated with NAT. Our study found that ALND did not reduce the occurrence of axillary recurrence or enhance overall survival. It is currently uncertain which patients benefit from axillary dissection.

CBCRisk-Black: a personalized contralateral breast cancer risk prediction model for black women.

PURPOSE: Black breast cancer (BC) survivors have a higher risk of developing contralateral breast cancer (CBC) than Whites. Existing CBC risk prediction tools are developed based on mostly White women. To address this racial disparity, it is crucial to develop tools tailored for Black women to help them inform about their actual risk of CBC. METHODS: We propose an absolute risk prediction model, CBCRisk-Black, specifically for Black BC patients. It uses data on Black women from two sources: Breast Cancer Surveillance Consortium (BCSC) and Surveillance, Epidemiology, and End Results (SEER). First, a matched lasso logistic regression model for estimating relative risks (RR) is developed. Then, it is combined with relevant hazard rates and attributable risks to obtain absolute risks. Six-fold cross-validation is used to internally validate CBCRisk-Black. We also compare CBCRisk-Black with CBCRisk, an existing CBC risk prediction model. RESULTS: The RR model uses data from BCSC on 744 Black women (186 cases). CBCRisk-Black has four risk factors (RR compared to baseline): breast density (2.13 for heterogeneous/extremely dense), family history of BC (2.28 for yes), first BC tumor size (2.14 for T3/T4, 1.56 for TIS), and age at first diagnosis of BC (1.41 for < 40). The area under the receiver operating characteristic curve (AUC) for 3- and 5-year predictions are 0.72 and 0.65 for CBCRisk-Black while those are 0.65 and 0.60 for CBCRisk. CONCLUSION: CBCRisk-Black may serve as a useful tool to clinicians in counseling Black BC patients by providing a more accurate and personalized CBC risk estimate.

Underutilization of Needle Biopsy Before Breast Surgery: A Measure of Low-Value Care.

BACKGROUND: Breast core needle biopsy (CNB) can obviate the need for breast surgery in patients with an unknown breast lesion; however, variation in compliance with this guideline may represent a disparity in health care and a surrogate measure of unnecessary surgery. We evaluated variation in breast CNB rates prior to initial breast cancer surgery. METHODS: We performed a retrospective analysis using Medicare claims from 2015 to 2017 to evaluate the proportion of patients who received a CNB within 6 months prior to initial breast cancer surgery. Outlier practice pattern was defined as a preoperative CNB rate ≤ 70%. Logistic regression was used to evaluate surgeon characteristics associated with outlier practice pattern. RESULTS: We identified 108,935 female patients who underwent initial breast cancer surgery performed by 3229 surgeons from July 2015 to June 2017. The mean CNB rate was 86.7%. A total of 7.7% of surgeons had a CNB performed prior to initial breast surgery ≤ 70% of the time, and 2.0% had a CNB performed ≤ 50% of the time. Outlier breast surgeons were associated with practicing in a micropolitan area (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.29-2.73), in the South (OR 1.84, 95% CI 1.20-2.84) or West region (OR 1.78, 95% CI 1.11-2.86), > 20 years in practice (OR 1.52, 95% CI 1.09-2.11), and low breast cancer surgery volume (< 30 cases in the study period; OR 4.03, 95% CI 2.75-5.90). CONCLUSIONS: Marked variation exists in whether a breast core biopsy is performed prior to initial breast surgery, which may represent unnecessary surgery on individual patients. Providing surgeon-specific feedback on guideline compliance may reduce unwarranted variation.

Breast cancer progression when definitive surgery is delayed.

Deferment of definitive surgery for some breast cancers has been proposed as a way to conserve hospital resources during the COVID-19 pandemic. However, it is currently unknown which, if any, breast cancers are capable of progressing during a few to several months of observation. The difference between clinical size at diagnosis and final pathology size was assessed in 315 stage I-III primary invasive breast cancer patients who were divided into three groups based on the time between diagnosis and definitive surgery. Size differences over time were used to estimate specific growth rates. Compared with the group with ≤60 days between diagnosis and surgery, tumor growth was observed for 12% of tumors in the 61- to 120-day group and 17% of tumors in the >120-day group (p for trend = 0.032). Significantly greater specific growth rates were observed for tumors >2 cm by pathology measurement and for pathology node-positive patients (p < 0.0001 and p = 0.006, respectively). Specific growth rates were significantly greater for luminal B breast cancers than for luminal A breast cancers (p = 0.029) but not for triple-negative or HER2-positive breast cancers not selected for neo-adjuvant chemotherapy. There was no evidence of nodal progression with surgery delay. Fewer than 20% of stage I-III breast cancers not selected for neo-adjuvant chemotherapy evidence size progression during follow-up periods ranging from 61 to 294 days. Clinical-pathological features cannot reliably predict which tumors will grow. Luminal B phenotype was the only clinical variable known at the time of diagnosis that strongly predicted growth. If resource limitations mandate prioritization schemes for breast cancer surgery, luminal B breast cancer may be the highest priority.

Tomosynthesis-Guided Vacuum-Assisted Breast Biopsy of Architectural Distortion Without a Sonographic Correlate: A Retrospective Review.

BACKGROUND. Digital breast tomosynthesis-guided vacuum-assisted breast biopsy (DBT VAB) allows biopsy of findings seen better or exclusively on digital breast tomosynthesis (DBT), including architectural distortion. Although architectural distortion with an associated sonographic mass correlate has a high risk of malignancy, limited data describe the radiologic-pathologic correlation of tomosynthesis-detected architectural distortion without a sonographic correlate. OBJECTIVE. This study evaluates the malignancy rate of architectural distortions without a sonographic correlate that undergo DBT VAB and provides radiologic-pathologic correlation for benign, high-risk, and malignant entities that are associated with architectural distortion. METHODS. We retrospectively reviewed imaging, as well as pathology slides and/or reports, for DBT VABs performed for architectural distortion without a sonographic correlate at a single institution between June 1, 2017, and January 15, 2020. According to the correlative histopathology, cases were categorized as benign, high risk, or malignant, and specific histopathologic diagnoses were summarized. RESULTS. During the study period, 142 patients (mean age, 59 years) underwent DBT VAB for 151 unique architectural distortions without a sonographic correlate. DBT VAB revealed a malignant diagnosis in 27 (18%), a high-risk lesion in 50 (33%), and a benign diagnosis in 74 (49%). Two cases of atypical ductal hyperplasia were upgraded to malignancy, resulting in a final malignancy rate of 19% (n = 29/151). Most malignant lesions were invasive carcinomas (83%, n = 24/29); most invasive carcinomas were of lobular subtype (54%, n = 13/24). Most high-risk lesions were radial scars/complex sclerosing lesions (62%, n = 31/50). Most benign results represented fibrocystic change (66%, n = 49/74). A subset (11%, n = 8/74) of benign results were considered discordant and subsequently excised, with none representing malignancy. CONCLUSION. The final malignancy rate of 19% in architectural distortion without a sonographic correlate justifies a recommendation for biopsy using DBT VAB. CLINICAL IMPACT. Our results highlight the utility of DBT VAB in the era of DBT. The detailed radiologic-pathologic correlations will assist radiologists in assessing concordance when performing DBT VAB for architectural distortions and provide a reference for future patient management.

Association of Event-Free and Distant Recurrence-Free Survival With Individual-Level Pathologic Complete Response in Neoadjuvant Treatment of Stages 2 and 3 Breast Cancer: Three-Year Follow-up Analysis for the I-SPY2 Adaptively Randomized Clinical Trial.

Importance: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial. Objective: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. Design, Setting, and Participants: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019. Interventions: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide. Main Outcomes and Measures: Pathologic complete response and 3-year EFS and DRFS. Results: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. Conclusions and Relevance: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.

Legacy Genetic Testing Results for Cancer Susceptibility: How Common are Conflicting Classifications in a Large Variant Dataset from Multiple Practices?

PURPOSE: The classification of germline variants may differ between labs and change over time. We apply a variant harmonization tool, Ask2Me VarHarmonizer, to map variants to ClinVar and identify discordant variant classifications in a large multipractice variant dataset. METHODS: A total of 7496 variants sequenced between 1996 and 2019 were collected from 11 clinical practices. Variants were mapped to ClinVar, and lab-reported and ClinVar variant classifications were analyzed and compared. RESULTS: Of the 4798 unique variants identified, 3699 (77%) were mappable to ClinVar. Among mappable variants, variants of unknown significance (VUS) accounted for 74% of lab-reported classifications and 60% of ClinVar classifications. Lab-reported and ClinVar discordances were present in 783 unique variants (21.2% of all mappable variants); 121 variants (2.5% of all unique variants) had within-practice lab-reported discordances; and 56 variants (1.2% of all unique variants) had lab-reported discordances across practices. The unmappable variants were associated with a higher proportion of lab-reported pathogenic classifications (50% vs. 21%, p < 0.0001) and a lower proportion of lab-reported VUS classifications (46% vs. 74%, p < 0.0001). CONCLUSIONS: Our study shows that discordant variant classification occurs frequently, which may lead to inappropriate recommendations for prophylactic treatments or clinical management.

Management of the clinically positive axilla.

Axillary dissection has been the standard of care for any patient with clinically positive lymph nodes at initial breast cancer presentation. However, modern neo-adjuvant therapies can convert positive nodes to negative nodes, especially in the setting of HER2-positive disease. Accurate axillary staging can be achieved after neo-adjuvant therapy in initially node-positive patients using dual tracer lymphatic mapping, removal of three or more lymph nodes, and confirmation of excision of the previously biopsied and clipped lymph node. Currently accruing clinical trials are designed to determine which patients can safely avoid axillary dissection and/or axillary radiation.

Consensus Guidelines on Genetic` Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons.

BACKGROUND: The purpose of this consensus guideline is to outline recommendations for genetic testing that medical professionals can use to assess hereditary risk for breast cancer. METHODS: Literature review included large datasets, basic and clinical science publications, and recent updated national guidelines. Genetic testing to assess hereditary risk of cancer is a complex, broad, and dynamic area of medical research. The dominant focus of this guideline is limited in scope to breast cancer. RESULTS: There is a lack of consensus among experts regarding which genes among many should be tested in different clinical scenarios. There is also variation in the degree of consensus regarding the understanding of risk and appropriate clinical management of mutations in many genes. CONCLUSIONS: Genetic testing should be made available to all patients with a personal history of breast cancer. Recent data are reviewed that support genetic testing being offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment recommendations. Patients who had genetic testing previously may benefit from updated testing. Genetic testing should be made available to patients without a history of breast cancer who meet National Comprehensive Cancer Network guidelines. Finally, variants of uncertain significance are not clinically actionable and these patients should be managed based on their individual risk factors.

Survival and Disease Recurrence Rates among Breast Cancer Patients following Mastectomy with or without Breast Reconstruction.

BACKGROUND: Concerns have been expressed about the oncologic safety of breast reconstruction following mastectomy for breast cancer. This study aimed to evaluate the association of breast reconstruction with breast cancer recurrence, and 5-year survival among breast cancer patients. METHODS: The authors analyzed data from The Johns Hopkins Hospital comprehensive cancer registry, comparing mastectomy-only to postmastectomy breast reconstruction in breast cancer patients to evaluate differences in breast cancer recurrence and 5-year survival. Kaplan-Meier curves were used to compare unadjusted estimates of survival or disease recurrence. Data were modeled through Cox proportional hazards regression, using as outcomes time to death from any cause or time to cancer recurrence. RESULTS: The authors analyzed data on 1517 women who underwent mastectomy for breast cancer at The Johns Hopkins hospital between 2003 and 2015. Of these, 504 (33.2 percent) underwent mastectomy only and 1013 (66.8 percent) underwent mastectomy plus immediate breast reconstruction. Women were followed up for a median of 5.1 years after diagnosis. There were 132 deaths and 100 breast cancer recurrences. A comparison of Kaplan-Meier survival estimates demonstrated a survival benefit among patients undergoing mastectomy plus reconstruction. After adjusting for various clinical and socioeconomic variables, there was still an overall survival benefit associated with breast reconstruction which, however, was not statistically significant (hazard ratio, 0.78; 95 percent CI, 0.53 to 1.13). Patients who underwent reconstruction had a similar rate of recurrence compared to mastectomy-only patients (hazard ratio, 1.08; 95 percent CI, 0.69 to 1.69). CONCLUSION: This study suggests that breast reconstruction does not have a negative impact on either overall survival or breast cancer recurrence rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Germline Genetic Testing: What the Breast Surgeon Needs to Know.

PURPOSE: The American Society of Breast Surgeons (ASBrS) sought to provide educational guidelines for breast surgeons on how to incorporate genetic information and genomics into their practice. METHODS: A comprehensive nonsystematic review was performed of selected peer-reviewed literature. The Genetics Working Group of the ASBrS convened to develop guideline recommendations. RESULTS: Clinical and educational guidelines were prepared to outline the essential knowledge for breast surgeons to perform germline genetic testing and to incorporate the findings into their practice, which have been approved by the ASBrS Board of Directors. RECOMMENDATIONS: Thousands of women in the USA would potentially benefit from genetic testing for BRCA1, BRCA2, and other breast cancer genes that markedly increase their risk of developing breast cancer. As genetic testing is now becoming more widely available, women should be made aware of these tests and consider testing. Breast surgeons are well positioned to help facilitate this process. The areas where surgeons need to be knowledgeable include: (1) identification of patients for initial breast cancer-related genetic testing, (2) identification of patients who tested negative in the past but now need updated testing, (3) initial cancer genetic testing, (4) retesting of patients who need their genetic testing updated, (5) cancer genetic test interpretation, posttest counseling and management, (6) management of variants of uncertain significance, (7) cascade genetic testing, (8) interpretation of genetic tests other than clinical cancer panels and the counseling and management required, and (9) interpretation of somatic genetic tests and the counseling and management required.

Change in health-related quality of life in older women after diagnosis of a small breast cancer.

BACKGROUND: Screening mammography reduces breast cancer mortality at the cost of frequent false-positive results that lead to unnecessary medical procedures, and the treatment of indolent breast cancers that would never threaten life or health. Earlier diagnosis generally permits less disruptive treatment, but it is possible that even the diagnosis of a very small breast cancer could significantly adversely impact health-related quality of life (HRQOL) in older women. METHODS: The authors compared changes in HRQOL measured by either the Medical Outcomes Study 36-Item Short Form (SF-36) or the Veterans Rand 12-item Health Survey (VR-12) between 198 women diagnosed with in situ or invasive breast cancer measuring ≤1 cm and 36,814 matched controls using the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registry linked with the Medicare Health Outcomes Survey. RESULTS: The mean age of the cases and controls was 75 years. The SF-36/VR-12 physical component score 12 was found to decrease by 1.6 points between the baseline and follow-up surveys for the controls compared with 3.2 points for women diagnosed with small breast cancers (P = .016). A 2-point decline is recognized as the minimally significant difference for this measure. On multivariable analysis, diagnosis of a small breast cancer was found to be one of the strongest predictors of a significant decrease in both the physical and mental domains of HRQOL (P = .012 and P = .023, respectively). CONCLUSIONS: Receiving the diagnosis of even a very small breast cancer significantly impacts the physical and mental domains of HRQOL in older women. This finding can inform discussions regarding the relative benefits and costs of screening mammography in older women.

Surgeon Re-Excision Rates after Breast-Conserving Surgery: A Measure of Low-Value Care.

BACKGROUND: To better understand re-excision practice patterns after breast-conserving therapy (BCT), we evaluated variation in surgeon-specific re-excision rates and associated factors. STUDY DESIGN: We performed a retrospective analysis using Medicare claims from 2012 to 2018 to identify patients undergoing BCT and subsequent breast resection procedures within 12 months. We compared rates before and after the 2014 "no tumor on ink" consensus guideline. A hierarchical logistic regression model was also used to evaluate patient and physician characteristics associated with re-excision. RESULTS: We identified 291,065 female Medicare beneficiaries who underwent an initial BCT procedure, of which 19.0% had a re-excision. The overall re-excision rate was 22.1% in the pre-guideline period and 17.2% in the post-guideline period. For the 5,337 physicians that performed more than 10 initial BCT procedures during the study period, their physician-level re-excision rate ranged from 0% to 91.7% (median 18.2%). In total, 17.5% of the physicians had a re-excision rate greater than the expert consensus cutoff of 30%. The percentage of outlier physicians decreased from 22.2% in 2012 to 8.8% in 2017. High surgeon volume of BCT was associated with a lower re-excision odds (≥51 cases vs ≤20 cases: adjusted odds ratio 0.78; 95% CI 0.74 to 0.82; 21 to 50 cases vs ≤20 cases: adjusted odds ratio 0.92; 95% CI 0.88 to 0.96). Patient factors associated with decreased odds of re-excision were age older than 75 years and Northeast region of the US (adjusted odds ratio 0.93; 95% CI 0.89 to 0.98). CONCLUSIONS: Marked variation exists in surgeon re-excision rates among patients undergoing BCT, which might represent unnecessary operations for patients and a financial burden to the healthcare system. Formalizing a re-excision frequency metric could have implications for quality improvement and data-driven surgeon feedback aimed at reducing unwarranted variation.

The Use of Tumescent Technique in Mastectomy and Related Complications: A Meta-Analysis.

BACKGROUND: Postoperative skin necrosis in surgical patients is costly to hospitals and health care providers. Tumescent dissection technique is commonly used in mastectomy and immediate breast reconstruction, as it helps reduce blood loss; however, it may increase the risk of mastectomy skin flap necrosis. In this context, the authors have conducted a systematic review of the literature to perform a meta-analysis of the relationship between tumescent technique in mastectomy with or without breast reconstruction and complication rates. METHODS: The authors screened the PubMed (1966 to 2016), Scopus (2004 to 2016), Embase (1966 to 2016), and Web of Science (1964 to 2016) databases for relevant articles through March 30, 2017. The authors included studies on the use of tumescent technique in the context of mastectomy with or without immediate breast reconstruction. The primary outcome the authors evaluated was the rate of skin flap necrosis; the secondary outcomes were the rates of breast hematomas and infections. Because of the heterogeneity of the studies, the authors performed a meta-analysis using the random effects model. RESULTS: After screening, the authors evaluated five studies including 3982 mastectomies. Mastectomies performed under the preoperative application of tumescent solution had statistically higher rates of skin flap necrosis overall (p = 0.03) and major (p < 0.01) and minor skin necrosis (p = 0.03). However, the rates of hematoma and infection were not correlated with the use of tumescent technique. CONCLUSIONS: The authors' systematic review of the literature provides a better understanding of the consequences of the application of tumescent technique in mastectomy. The authors' findings suggest that tumescent technique may increase the risk of skin necrosis in mastectomy with or without breast reconstruction.

Dose-dependent effect of mammographic breast density on the risk of contralateral breast cancer.

PURPOSE: Increased mammographic breast density is a significant risk factor for breast cancer. It is not clear if it is also a risk factor for the development of contralateral breast cancer. METHODS: The data were obtained from Breast Cancer Surveillance Consortium and included women diagnosed with invasive breast cancer or ductal carcinoma in situ between ages 18 and 88 and years 1995 and 2009. Each case of contralateral breast cancer was matched with three controls based on year of first breast cancer diagnosis, race, and length of follow-up. A total of 847 cases and 2541 controls were included. The risk factors included in the study were mammographic breast density, age of first breast cancer diagnosis, family history of breast cancer, anti-estrogen treatment, hormone replacement therapy, menopausal status, and estrogen receptor status, all from the time of first breast cancer diagnosis. Both univariate analysis and multivariate conditional logistic regression analysis were performed. RESULTS: In the final multivariate model, breast density, family history of breast cancer, and anti-estrogen treatment remained significant with p values less than 0.01. Increasing breast density had a dose-dependent effect on the risk of contralateral breast cancer. Relative to 'almost entirely fat' category of breast density, the adjusted odds ratios (and p values) in the multivariate analysis for 'scattered density,' 'heterogeneously dense,' and 'extremely dense' categories were 1.65 (0.036), 2.10 (0.002), and 2.32 (0.001), respectively. CONCLUSION: Breast density is an independent and significant risk factor for development of contralateral breast cancer. This risk factor should contribute to clinical decision making.

Validation of a personalized risk prediction model for contralateral breast cancer.

PURPOSE: Women diagnosed with unilateral breast cancer are increasingly choosing to remove their other unaffected breast through contralateral prophylactic mastectomy (CPM) to reduce the risk of contralateral breast cancer (CBC). Yet a large proportion of CPMs are believed to be medically unnecessary. Thus, there is a pressing need to educate patients effectively on their CBC risk. We had earlier developed a CBC risk prediction model called CBCRisk based on eight personal risk factors. METHODS: In this study, we validate CBCRisk on independent clinical data from the Johns Hopkins University (JH) and MD Anderson Cancer Center (MDA). Women whose first breast cancer diagnosis was either invasive and/or ductal carcinoma in situ and whose age at first diagnosis was between 18 and 88 years were included in the cohorts because CBCRisk was developed specifically for these women. A woman who develops CBC is called a case whereas a woman who does not is called a control. The cohort sizes are 6035 (with 117 CBC cases) for JH and 5185 (with 111 CBC cases) for MDA. We computed the relevant calibration and validation measures for 3- and 5-year risk predictions. RESULTS: We found that the model performs reasonably well for both cohorts. In particular, area under the receiver-operating characteristic curve for the two cohorts range from 0.61 to 0.65. CONCLUSIONS: With this independent validation, CBCRisk can be used confidently in clinical settings for counseling BC patients by providing their individualized CBC risk. In turn, this may potentially help alleviate the rate of medically unnecessary CPMs.