The Clinical Utility of a 7-Gene Biosignature on Radiation Therapy Decision Making in Patients with Ductal Carcinoma In Situ Following Breast-Conserving Surgery: An Updated Analysis of the DCISionRT® PREDICT Study.

BACKGROUND: Breast-conserving surgery (BCS) followed by adjuvant radiotherapy (RT) is a standard treatment for ductal carcinoma in situ (DCIS). A low-risk patient subset that does not benefit from RT has not yet been clearly identified. The DCISionRT test provides a clinically validated decision score (DS), which is prognostic of 10-year in-breast recurrence rates (invasive and non-invasive) and is also predictive of RT benefit. This analysis presents final outcomes from the PREDICT prospective registry trial aiming to determine how often the DCISionRT test changes radiation treatment recommendations. METHODS: Overall, 2496 patients were enrolled from February 2018 to January 2022 at 63 academic and community practice sites and received DCISionRT as part of their care plan. Treating physicians reported their treatment recommendations pre- and post-test as well as the patient's preference. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendation. The impact of the test on RT treatment recommendation was physician specialty, treatment settings, individual clinical/pathological features and RTOG 9804 like criteria. Multivariate logisitc regression analysis was used to estimate the odds ratio (ORs) for factors associated with the post-test RT recommendations. RESULTS: RT recommendation changed 38% of women, resulting in a 20% decrease in the overall recommendation of RT (p < 0.001). Of those women initially recommended no RT (n = 583), 31% were recommended RT post-test. The recommendation for RT post-test increased with increasing DS, from 29% to 66% to 91% for DS <2, DS 2-4, and DS >4, respectively. On multivariable analysis, DS had the strongest influence on final RT recommendation (odds ratio 22.2, 95% confidence interval 16.3-30.7), which was eightfold greater than clinicopathologic features. Furthermore, there was an overall change in the recommendation to receive RT in 42% of those patients meeting RTOG 9804-like low-risk criteria. CONCLUSIONS: The test results provided information that changes treatment recommendations both for and against RT use in large population of women with DCIS treated in a variety of clinical settings. Overall, clinicians changed their recommendations to include or omit RT for 38% of women based on the test results. Based on published clinical validations and the results from current study, DCISionRT may aid in preventing the over- and undertreatment of clinicopathological 'low-risk' and 'high-risk' DCIS patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03448926 ( https://clinicaltrials.gov/study/NCT03448926 ).

The Clinical Utility of DCISionRT® on Radiation Therapy Decision Making in Patients with Ductal Carcinoma In Situ Following Breast-Conserving Surgery.

BACKGROUND: The role of radiation therapy (RT) following breast-conserving surgery (BCS) in ductal carcinoma in situ (DCIS) remains controversial. Trials have not identified a low-risk cohort, based on clinicopathologic features, who do not benefit from RT. A biosignature (DCISionRT®) that evaluates recurrence risk has been developed and validated. We evaluated the impact of DCISionRT on clinicians' recommendations for adjuvant RT. METHODS: The PREDICT study is a prospective, multi-institutional, observational registry in which patients underwent DCISionRT testing. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendations. RESULTS: Overall, 539 women were included in this study. Pre DCISionRT testing, RT was recommended to 69% of patients; however, post-testing, a change in the RT recommendation was made for 42% of patients compared with the pre-testing recommendation; the percentage of women who were recommended RT decreased by 20%. For women initially recommended not to receive an RT pre-test, 35% had their recommendation changed to add RT following testing, while post-test, 46% of patients had their recommendation changed to omit RT after an initial recommendation for RT. When considered in conjunction with other clinicopathologic factors, the elevated DCISionRT score risk group (DS > 3) had the strongest association with an RT recommendation (odds ratio 43.4) compared with age, grade, size, margin status, and other factors. CONCLUSIONS: DCISionRT provided information that significantly changed the recommendations to add or omit RT. Compared with traditional clinicopathologic features used to determine recommendations for or against RT, the factor most strongly associated with RT recommendations was the DCISionRT result, with other factors of importance being patient preference, tumor size, and grade.

TARGIT-R (Retrospective): 5-Year Follow-Up Evaluation of Intraoperative Radiation Therapy (IORT) for Breast Cancer Performed in North America.

BACKGROUND: Intraoperative radiation therapy (IORT) has been investigated for patients with low-risk, early-stage breast cancer. The The North American experience was evaluated by TARGIT-R (retrospective) to provide outcomes for patients treated in "real-world" clinical practice with breast IORT. This analysis presents a 5-year follow-up assessment. METHODS: TARGIT-R is a multi-institutional retrospective registry of patients who underwent lumpectomy and IORT between the years 2007 and 2013. The primary outcome of the evaluation was ipsilateral breast tumor recurrence (IBTR). RESULTS: The evaluation included 667 patients with a median follow-up period of 5.1 years. Primary IORT (IORT at the time of lumpectomy) was performed for 72%, delayed IORT (after lumpectomy) for 3%, intended boost for 8%, and unintended boost (primary IORT followed by whole-breast radiation) for 17% of the patients. At 5 years, IBTR was 6.6% for all the patients, with 8% for the primary IORT cohort and 1.7% for the unintended-boost cohort. No recurrences were identified in the delayed IORT or intended-boost cohorts. Noncompliance with endocrine therapy (ET) was associated with higher IBTR risk (hazard ratio [HR], 3.67). Patients treated with primary IORT who were complaint with ET had a 5-year IBTR rate of 3.9%. CONCLUSION: The local recurrence rates in this series differ slightly from recent results of randomized IORT trials and are notably higher than in previous published studies using whole-breast radiotherapy for similar patients with early-stage breast cancer. Understanding differences in this retrospective series and the prospective trials will be critical to optimizing patient selection and outcomes going forward.

Delivery of nipple-sparing mastectomy within a single healthcare system: The impact of provider preferences.

Nipple-sparing mastectomy (NSM) offers superior esthetic outcomes without sacrificing oncologic safety for select patients requiring mastectomy. While disparities in oncologic care are well established, no study to date has investigated equitable delivery of the various mastectomy types. The objective of this study is to examine multilevel factors related to the distribution of NSM. Patients undergoing mastectomy between 2014 and 2018 across eight hospitals in a single healthcare system were retrospectively reviewed. Patients were categorized by mastectomy type-NSM or other mastectomy (OM). Patient information such as age, race, comorbidities, and median income by ZIP code was collected. Disease characteristics, such as mastectomy weight, breast cancer stage, and treatment history, were identified. Provider and system-level variables, such as specific provider, hospital of operation, and insurance status, were determined. Bivariate analysis was used to identify variables for inclusion in a backward multivariable model. A cohort of 1202 mastectomy patients was identified, with 388 receiving NSM. The average age was 55.8 years (NSM: 48.8, OM: 59.1, P < .001). 39.8% of white patients (n = 242) and 20.0% of African American patients (n = 88) received NSM (P < .001). Average mastectomy weight was 384.3 (SD 195.7) in the NSM group, compared to 839.4 (SD 521.1) in the OM group (P < .001). 41.4% (n = 359) of patients treated at academic centers, and 6.9% (n = 21) of patients treated at community centers received NSM (P < .001). In the multivariate model, the factor with the largest impact on NSM was specific provider. Odds of NSM decreased by 76%-88% for certain surgeons, while odds increased by 63 times for one surgeon. This study utilizes a large multi-institutional database to highlight disparities in NSM delivery. Expectedly, younger, relatively healthy patients, with smaller breast size were more likely to undergo NSM, in accordance with surgical guidelines. However, when all other factors were controlled, provider preferences played the most significant role in NSM delivery rates. These findings demonstrate the need for practice reexamination to ensure equitable access to NSM.

Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. the COVID-19 pandemic breast cancer consortium.

The COVID-19 pandemic presents clinicians a unique set of challenges in managing breast cancer (BC) patients. As hospital resources and staff become more limited during the COVID-19 pandemic, it becomes critically important to define which BC patients require more urgent care and which patients can wait for treatment until the pandemic is over. In this Special Communication, we use expert opinion of representatives from multiple cancer care organizations to categorize BC patients into priority levels (A, B, C) for urgency of care across all specialties. Additionally, we provide treatment recommendations for each of these patient scenarios. Priority A patients have conditions that are immediately life threatening or symptomatic requiring urgent treatment. Priority B patients have conditions that do not require immediate treatment but should start treatment before the pandemic is over. Priority C patients have conditions that can be safely deferred until the pandemic is over. The implementation of these recommendations for patient triage, which are based on the highest level available evidence, must be adapted to current availability of hospital resources and severity of the COVID-19 pandemic in each region of the country. Additionally, the risk of disease progression and worse outcomes for patients need to be weighed against the risk of patient and staff exposure to SARS CoV-2 (virus associated with the COVID-19 pandemic). Physicians should use these recommendations to prioritize care for their BC patients and adapt treatment recommendations to the local context at their hospital.

Contralateral axillary sentinel lymph node in breast cancer recurrence.

The rare but significant reports of aberrant lymph node drainage outside of the ipsilateral axilla in patients with breast cancer necessitate a review of the staging and treatment strategies for these patients. Current staging modalities continue to describe this phenomenon as a stage IV cancer, which could have profound implications for clinical management. We report a case of a patient with recurrent right breast invasive ductal carcinoma whose preoperative lymphoscintigraphy revealed sentinel lymph node drainage to the contralateral axilla. This discovery subsequently altered surgical planning and her ultimate stage.

Does surgeon handedness or experience predict immediate complications after mastectomy? A critical examination of outcomes in a single health system.

Surgeons often seek to perfect their technical dexterity, and hand dominance of the surgeon is an important factor given the constraints of operative field laterality. However, experience often dictates how surgeons are able to compensate. While surgeons have experienced preference for the ipsilateral breast, the impact of surgeon handedness, experience, and volume has not been directly examined in a single study. A retrospective chart review of five breast surgeons (2 LHD) at a single institution identified 365 mastectomy patients, totaling 594 breasts, between January 2015 and June 2018. The breasts were identified as ipsilateral or contralateral based on the surgeons' handedness. Surgeons were grouped based on length of surgical experience, three with ≥15 years and two with <15 years. Surgeons with greater experience were the highest volume surgeons in this series. Data included patient demographics, breast and oncologic history, surgical techniques, and surgical outcomes including complications. A total of 270 nonprophylactic and 324 prophylactic mastectomies were identified, of which 529 were performed by surgeons with greater than 15 years of experience and 65 by surgeons with less than 15 years. The overall complication rate was 33.5% (n = 199), of which 18.0% (n = 107) were on the ipsilateral breast and 15.5% (n = 92) were on the contralateral breast. 9.1% of complications required re-operation (n = 54). The odds of any complication on the ipsilateral breast were 2.9 times higher than complications on the contralateral breast when looking exclusively at surgeons with <15 years of experience (P = .0353, OR = 2.92, 1.06-8.03). Surgeons with <15 years of experience have a 2.71 (P = .05, OR 2.71, 1.361-5.373) increase in any ischemic complication and a 16 times (P < .0001, OR = 16.01, 5.038-50.933) increase in major operative ischemic complications. Our study finds that surgeons with less than 15 years of surgical experience have a 2.9 times higher rate of overall complication when operating on the ipsilateral breast. However, years of experience and surgeon volume have a much greater impact on any and ischemic complications after mastectomy.

Factors contributing to persistent rates of contralateral prophylactic mastectomy in breast cancer patients: Examination of 1051 mastectomies across a single health system.

The American Society of Breast Surgeons (ASBrS) outlined definitive guidelines for contralateral prophylactic mastectomy (CPM) in 2016. Despite this, rates of CPM have remained steady. The objective of this study was to identify factors contributing to persistent over-delivery of CPM. Breast cancer patients across 8 hospitals in a single healthcare system from 2014 to 2018 were retrospectively reviewed. The patients were divided according to whether they received nonindicated CPMs versus other mastectomy types. Nonindicated CPM were those procedures not meeting ASBrS consensus guidelines for recommended patients. CPM rate was calculated for each year in the study period. Patient, disease, provider, and system level factors were obtained. Bivariate analysis was used to identify variables for inclusion in a backward multivariable model. A total of 1,051 patients were analyzed. Nonindicated CPM rates by year remained steady throughout the time period (P = .391). In multivariable regression, patient, disease, and provider level factors were associated with odds of undergoing CPM. Every unit increase in age was associated with a 4% reduction in odds of undergoing CPM (CI 0.941-0.986). Stage 3 breast cancer compared to stage 1 had 53% lower odds of CPM (CI 0.288-0.757). Implant-based breast reconstruction had 2.9-fold higher odds of CPM compared to no reconstruction (CI 1.476-5.551). No system level factors were statistically significant. CPM rates have not notably decreased since the ASBrS consensus statement with certain patient and provider factors impacting persistent overuse of CPM. These results inform oncologic and reconstructive providers of factors contributing to continued use of a nonindicated procedure.

Neoadjuvant Chemotherapy and Nipple-Sparing Mastectomy: Timing and Postoperative Complications.

BACKGROUND: As the demand for nipple-sparing mastectomy (NSM) increases and surgeons expand the eligibility criteria, a subset of patients may become candidates following neoadjuvant chemotherapy (NACT). However, the impact of NACT on postoperative complications remains unclear as the current literature is discordant. METHODS: A single-institution, retrospective chart review was performed on patients undergoing NSM from 1989 to 2017. Patient demographics, surgical intervention, systemic treatment, and complication rates were collected. Primary outcomes were 30-day postoperative complications, including nipple-areolar necrosis, skin flap necrosis, infection, wound dehiscence, hematoma, and seroma. Secondary outcomes included characterization of the timing between chemotherapy and surgical intervention, and the impact on complication rates. Each breast was considered independently for analysis, and breasts undergoing either NACT or primary surgery (PS) were compared. RESULTS: Of the 832 breasts included, 88 (10.6%) received NACT and 744 (89.4%) underwent PS. Baseline complication rates were not significantly different between the NACT group and the PS group (5.7% vs. 10.6%; p = 0.119). When controlling for age, body mass index (BMI), smoking, and prior radiation, NACT was not a predictor of complications. Time from completion of NACT to PS occurred at a median of 40.5 days (interquartile range 31.3-55.3), and decreased intervals were not associated with increased complication rates. CONCLUSIONS: Postoperative complications following NSM in patients completing NACT are comparable with those receiving PS. Patients undergoing NACT do not have a significantly increased risk of necrosis, unintended reoperations, or nipple loss. NACT should not be considered a contraindication for NSM.

Positive Nipple Margin After Nipple-Sparing Mastectomy: An Alternative and Oncologically Safe Approach to Preserving the Nipple-Areolar Complex.

BACKGROUND: The aim of this study is to describe a less aggressive approach to management of positive nipple margin following nipple-sparing mastectomy (NSM), allowing for preservation of the nipple-areolar complex (NAC). STUDY DESIGN: A single-institution retrospective chart review was performed for patients undergoing NSM from 1989 to 2017. Positive nipple margin was defined as any residual invasive carcinoma or ductal carcinoma in situ (DCIS) within the additional nipple margin. Management included complete NAC removal, subareolar shave biopsy, or observation alone. Primary outcomes included rates of positive nipple margin and local recurrence. RESULTS: A total of 819 breasts underwent NSM, yielding a total of 32 breasts (3.9%) with positive nipple margin. Management included 11 (34.4%) subareolar shave biopsies, 15 (46.9%) complete NAC excisions, and 5 (15.6%) with observation alone, plus 1 (3.1%) lost to follow-up. Final pathology after subareolar shave biopsy did not reveal any residual disease, and no patients developed NAC necrosis or required NAC removal. Final pathology after NAC excision revealed 3 of 15 with additional disease (1 invasive ductal carcinoma, 2 DCIS). Of the five patients who had no subsequent intervention, tumor pathology was DCIS in all cases. One patient received adjuvant radiation therapy. Mean time to intervention was 3.7 ± 1.9 with mean follow-up of 2.9 years. CONCLUSIONS: Management of positive nipple margin after NSM with subareolar shave biopsy is a safe alternative to preserve the NAC.

Timing of radiation therapy in nipple-sparing mastectomy influences outcomes and patient-reported quality of life.

The aim of this study is to assess the complication profile and impact on patient-reported quality of life in those undergoing nipple-sparing mastectomy (NSM) with immediate breast reconstruction and subsequent prosthetic reconstruction in patients with prior breast radiation therapy (pRT) vs those receiving adjuvant post-mastectomy radiation therapy (PMRT). An IRB-approved, retrospective analysis was performed from 2002 to 2014 to identify NSM patients that underwent pRT or PMRT. A 22-item Likert scale questionnaire was administered by a third party to register patient-reported quality of life. Forty patients met criteria for outcomes analysis, and 30 patients answered the questionnaire. Mean age was 45.6 years old and mean follow-up was 3.8 years. Complication rates for the PMRT cohort were 61.9% vs 31.6% in the pRT cohort, P = .067, and those requiring operative intervention were PMRT 38.1% vs pRT 5.3%, P = .021. Nipple-areolar complex survival was 100% in the pRT vs 85.7% in the PMRT, P = .233. Breast-related quality of life scores were superior in the pRT group within multiple domains. Patients are more likely to develop complications requiring an operative intervention and have decreased breast-related quality of life when undergoing NSM with PMRT compared to patients undergoing NSM having received pRT.

TARGIT-R (Retrospective): North American Experience with Intraoperative Radiation Using Low-Kilovoltage X-Rays for Breast Cancer.

BACKGROUND: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America. METHODS: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed. RESULTS: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated. CONCLUSIONS: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

A randomized prospective study of lumpectomy margin assessment with use of MarginProbe in patients with nonpalpable breast malignancies.

BACKGROUND: The presence of tumor cells at the margins of breast lumpectomy specimens is associated with an increased risk of ipsilateral tumor recurrence. Twenty to 30 % of patients undergoing breast-conserving surgery require second procedures to achieve negative margins. This study evaluated the adjunctive use of the MarginProbe device (Dune Medical Devices Ltd, Caesarea, Israel) in providing real-time intraoperative assessment of lumpectomy margins. METHODS: This multicenter randomized trial enrolled patients with nonpalpable breast malignancies. The study evaluated MarginProbe use in addition to standard intraoperative methods for margin assessment. After specimen removal and inspection, patients were randomized to device or control arms. In the device arm, MarginProbe was used to examine the main lumpectomy specimens and direct additional excision of positive margins. Intraoperative imaging was used in both arms; no intraoperative pathology assessment was permitted. RESULTS: In total, 596 patients were enrolled. False-negative rates were 24.8 and 66.1 % and false-positive rates were 53.6 and 16.6 % in the device and control arms, respectively. All positive margins on positive main specimens were resected in 62 % (101 of 163) of cases in the device arm, versus 22 % (33 of 147) in the control arm (p < 0.001). A total of 19.8 % (59 of 298) of patients in the device arm underwent a reexcision procedure compared with 25.8 % (77 of 298) in the control arm (6 % absolute, 23 % relative reduction). The difference in tissue volume removed was not significant. CONCLUSIONS: Adjunctive use of the MarginProbe device during breast-conserving surgery improved surgeons' ability to identify and resect positive lumpectomy margins in the absence of intraoperative pathology assessment, reducing the number of patients requiring reexcision. MarginProbe may aid performance of breast-conserving surgery by reducing the burden of reexcision procedures for patients and the health care system.

Narrowing racial gaps in breast cancer chemotherapy initiation: the role of the patient-provider relationship.

Chemotherapy improves breast cancer survival but is underused more often in black than in white women. We examined associations between patient-physician relationships and chemotherapy initiation and timeliness of initiation among black and white patients. Women with primary invasive, non-metastatic breast cancer were recruited via hospitals (in Washington, DC and Detroit) and community outreach between July 2006 and April 2011. Data were collected via telephone interviews and medical records. Logistic regression models evaluated associations between chemotherapy initiation and independent variables. Since there were race interactions, analyses were race-stratified. Factors associated with time from surgery to chemotherapy initiation and delay of ≥90 days were evaluated with linear and logistic regressions, respectively. Among eligible women, 82.8 % were interviewed and 359 (90.9 %) of those had complete data. The odds of initiating chemotherapy were 3.26 times (95 % CI: 1.51, 7.06) higher among black women reporting greater communication with physicians (vs. lesser), after considering covariates. In contrast, the odds of starting chemotherapy were lower for white women reporting greater communication (vs. lesser) (adjusted OR 0.22, 95 % CI: 0.07, 0.73). The opposing direction of associations was also seen among the sub-set of black and white women with definitive clinical indications for chemotherapy. Among those initiating treatment, black women had longer mean time to the start of chemotherapy than whites (71.8 vs. 55.0 days, p = 0.005), but race was not significant after considering trust in oncologists, where initiation time decreased as trust increased, controlling for covariates. Black women were also more likely to delay ≥90 days than whites (27 vs. 8.3 %; p = 0.024), but this was not significant after considering religiosity. The patient-physician dyad and sociocultural factors may represent leverage points to improve chemotherapy patterns in black women.

A peer-led decision support intervention improves decision outcomes in black women with breast cancer.

Previous reports suggest that Black breast cancer patients receive less patient-centered cancer care than their White counterparts. Interventions to improve patient-centered care (PCC) in Black breast cancer patients are lacking. Seventy-six women with histologically confirmed breast cancer were recruited from the Washington, DC area. After a baseline telephone interview, women received an in-person decision support educational session led by a trained survivor coach. The coach used a culturally appropriate guidebook and decision-making model-TALK Back!(©) A follow-up assessment assessed participants' acceptability of the intervention and intermediate outcomes. After the intervention, participants reported increased: self-efficacy in communicating with providers (70 %) and self-efficacy in making treatment decisions (70 %). Compared to baseline scores, post-intervention communication with providers significantly increased (p= .000). This is the first outcome report of an intervention to facilitate PCC in Black breast cancer patients. Testing this intervention using RCTs or similar designs will be important next steps.

Breast cancer screening: clinical, radiologic, and biochemical.

Breast cancer screening is a highly complex and more recently a controversial topic. Conventional screening includes breast self-examination, clinical breast examination, and screening mammography. Several newer imaging modalities have been introduced into the screening armamentarium including breast magnetic resonance imaging and whole-breast automated ultrasound. Novel imaging techniques like positron emission mammography are currently under clinical investigation in the hopes of improving the sensitivity of breast cancer screening. In addition, the development of biochemical assays, which employ minimally invasive sampling are also promising.

Mutagen sensitivity, tobacco smoking and breast cancer risk: a case-control study.

UNLABELLED: Given the high incidence of breast cancer and that more than half of cases remain unexplained, the need to identify risk factors for breast cancer remains. Deficiencies in DNA repair capacity have been associated with cancer risk. The mutagen sensitivity assay (MSA), a phenotypic marker of DNA damage response and repair capacity, has been consistently shown to associate with the risk of tobacco-related cancers. METHODS: In a case-control study of 164 women with breast cancer and 165 women without the disease, we investigated the association between mutagen sensitivity and risk of breast cancer using bleomycin as the mutagen. RESULTS: High bleomycin sensitivity (>0.65 breaks per cell) was associated with an increased risk of breast cancer, with an adjusted odds ratio of 2.8 [95% confidence interval (CI) = 1.7-4.5]. Risk increased with greater number of bleomycin-induced chromosomal breaks (P(trend) = 0.01). The association between bleomycin sensitivity and breast cancer risk was greater for women who were black, premenopausal and ever smokers. Our data also suggest that bleomycin sensitivity may modulate the effect of tobacco smoking on breast cancer risk. Among women with hypersensitivity to bleomycin, ever smokers had a 1.6-fold increased risk of breast cancer (95% CI = 0.6-3.9, P for interaction between tobacco smoking and bleomycin sensitivity = 0.32). CONCLUSIONS: Increased bleomycin sensitivity is significantly associated with an increased risk of breast cancer in both pre- and postmenopausal women. Our observation that the effect of tobacco smoking on breast cancer risk may differ based on mutagen sensitivity status warrants further investigation.