The Incidence of Adjacent Synchronous Invasive Carcinoma and/or Ductal Carcinoma In Situ in Patients with Intraductal Papilloma without Atypia on Core Biopsy: Results from a Prospective Multi-Institutional Registry (TBCRC 034).

BACKGROUND: Available retrospective data suggest the upgrade rate for intraductal papilloma (IP) without atypia on core biopsy (CB) ranges from 0 to 12%, leading to variation in recommendations. We conducted a prospective multi-institutional trial (TBCRC 034) to determine the upgrade rate to invasive cancer (IC) or ductal carcinoma in situ (DCIS) at excision for asymptomatic IP without atypia on CB. METHODS: Prospectively identified patients with a CB diagnosis of IP who had consented to excision were included. Discordant cases, including BI-RADS > 4, and those with additional lesions requiring excision were excluded. The primary endpoint was upgrade to IC or DCIS by local pathology review with a predefined rule that an upgrade rate of ≤ 3% would not warrant routine excision. Sample size and confidence intervals were based on exact binomial calculations. Secondary endpoints included diagnostic concordance for IP between local and central pathology review and upgrade rates by central pathology review. RESULTS: The trial included116 patients (median age 56 years, range 24-82) and the most common imaging abnormality was a mass (n = 91, 78%). Per local review, 2 (1.7%) cases were upgraded to DCIS. In both of these cases central pathology review did not confirm DCIS on excision. Additionally, central pathology review confirmed IP without atypia in core biopsies of 85/116 cases (73%), and both locally upgraded cases were among them. CONCLUSION: In this prospective study of 116 IPs without atypia on CB, the upgrade rate was 1.7% by local review, suggesting that routine excision is not indicated for IP without atypia on CB with concordant imaging findings.

Impact of surgical complications on patient reported outcomes (PROs) following nipple sparing mastectomy.

INTRODUCTION: Nipple sparing mastectomy (NSM) is oncologically safe and provides excellent cosmetic outcomes. Complications after surgery may impact patient reported outcomes (PROs). We assessed the impact of complications on PROs after NSM. METHODS: We enrolled 63 patients (pts) who met eligibility criteria for NSM from September 2011 until August 2014. PROs were administered before surgery and at 1 year. Clinical data were collected from the electronic health record. Analyses were performed in SPSS Statistics for Windows (version 21.0). Pts with and without complications were compared using a one-way ANOVA. DATA: Sixty-three women were enrolled with a median age of 46. Postoperative complications requiring surgical treatment were seen in 10 patients (15.9%). Two patients required nipple excision due to necrosis (3.1%). No statistically significant differences in BREAST-Q scores were seen between pts with and without complications. CONCLUSION: Experiencing a complication after initial NSM surgery is not associated with decrease in PROs.

National trends of synchronous bilateral breast cancer incidence in the United States.

PURPOSE: Increase in breast cancer survivorship, advancements in diagnostic imaging and standardization of contralateral breast screening before breast cancer surgery have resulted in increased detection of contralateral breast cancer (CBC). The aim of this study was to assess national trends of synchronous bilateral breast cancer (sBBC) and metachronous bilateral breast cancer (mBBC) incidence in newly diagnosed breast cancer patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (1973-2014) was used to identify 11,177 women diagnosed with CBC. CBC was classified as sBBC when primary breast cancer in both breasts is diagnosed in the same year, or as mBBC, when diagnosed more than one year from primary breast cancer. Temporal trends in sBBC incidence were then evaluated using the Cochran-Armitage test for trend. RESULTS: Of the 11,177 women diagnosed with CBC, 4228 (38%) had sBBC and 6949 (62%) had mBBC. The incidence of sBBC increased significantly from 1.4% in 1975 to 2.9% in 2014 (p < 0.001). sBBC was more likely to be diagnosed as early stage in recent years (78% in 1975 vs. 90% in 2014 [p < 0.001]), and 69% of patients were treated with mastectomy in 2014. CONCLUSION: The number of sBBC has increased, and contralateral tumors are more likely to be detected at an early stage with the first primary breast cancer. Despite the early stage findings, most were treated with mastectomy. Further studies are needed to define the best therapy for patients with contralateral disease and optimal surveillance and detection methods.

Prognostic Significance of Residual Axillary Nodal Micrometastases and Isolated Tumor Cells After Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: The prognostic significance of low-volume residual nodal disease following neoadjuvant chemotherapy (NAC) is unknown. METHODS: Women with cT1-4N0-1 breast cancer treated with NAC were identified from Dana-Farber/Brigham and Women's Cancer Center (DFBWCC) and the National Cancer Database (NCDB). Disease-free survival (DFS) and overall survival (OS) estimates according to pathologic nodal status were calculated using the Kaplan-Meier method, with Cox proportional hazards regression used to assess the effect of clinical variables on survival outcomes. RESULTS: Among 967 DFBWCC patients, 27 (2.8%) had residual isolated tumor cells (ITCs) and 61 (6.3%) had micrometastases. Five-year DFS was significantly worse in those with residual ITCs (73.5%) and micrometastases (74.7%) relative to those who were ypN0 following NAC (88.4%, p < 0.001). On adjusted analysis, those with residual ITCs (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.20-3.81) and micrometastases (HR 2.14, 95% CI 1.20-3.81) had increased risk of recurrence relative to ypN0 patients. Among 35,536 NCDB patients, 543 (1.5%) had ITCs and 1132 (3.2%) had micrometastases. Five-year OS estimates were significantly worse with increasing residual nodal burden: ypN0, 88.9%; ypN0[i+], 82.8%; ypN1mi, 79.5%; ypN1, 77.6% (p < 0.001). Compared with patients with ypN0 disease, NCDB patients with ITCs and micrometastases had 1.9- and 2.2-fold risk of death (p < 0.001). On subgroup analysis, the effect of low-volume residual disease on mortality was most pronounced in patients with triple-negative and human epidermal growth factor receptor 2 (HER2)-positive disease. CONCLUSIONS: Low-volume residual nodal disease following NAC is associated with poorer DFS and OS relative to those who are node negative.

Feasibility of Intraoperative Breast MRI and the Role of Prone Versus Supine Positioning in Surgical Planning for Breast-Conserving Surgery.

We assessed the feasibility of supine intraoperative MRI (iMRI) during breast-conserving surgery (BCS), enrolling 15 patients in our phase I trial between 2012 and 2014. Patients received diagnostic prone MRI, BCS, pre-excisional supine iMRI, and postexcisional supine iMRI. Feasibility was assessed based on safety, sterility, duration, and image-quality. Twelve patients completed the study; mean duration = 114 minutes; all images were adequate; no complications, safety, or sterility issues were encountered. Substantial tumor-associated changes occurred (mean displacement = 67.7 mm, prone-supine metric, n = 7). We have demonstrated iMRI feasibility for BCS and have identified potential limitations of prone breast MRI that may impact surgical planning.

Patient Prognostic Score and Associations With Survival Improvement Offered by Radiotherapy After Breast-Conserving Surgery for Ductal Carcinoma In Situ: A Population-Based Longitudinal Cohort Study.

PURPOSE: Radiotherapy (RT) after breast-conserving surgery (BCS) is a standard treatment option for the management of ductal carcinoma in situ (DCIS). We sought to determine the survival benefit of RT after BCS on the basis of risk factors for local recurrence. PATIENTS AND METHODS: A retrospective longitudinal cohort study was performed to identify patients with DCIS diagnosed between 1988 and 2007 and treated with BCS by using SEER data. Patients were divided into the following two groups: BCS+RT (RT group) and BCS alone (non-RT group). We used a patient prognostic scoring model to stratify patients on the basis of risk of local recurrence. We performed a Cox proportional hazards model with propensity score weighting to evaluate breast cancer mortality between the two groups. RESULTS: We identified 32,144 eligible patients with DCIS, 20,329 (63%) in the RT group and 11,815 (37%) in the non-RT group. Overall, 304 breast cancer-specific deaths occurred over a median follow-up of 96 months, with a cumulative incidence of breast cancer mortality at 10 years in the weighted cohorts of 1.8% (RT group) and 2.1% (non-RT group; hazard ratio, 0.73; 95% CI, 0.62 to 0.88). Significant improvements in survival in the RT group compared with the non-RT group were only observed in patients with higher nuclear grade, younger age, and larger tumor size. The magnitude of the survival difference with RT was significantly correlated with prognostic score (P < .001). CONCLUSION: In this population-based study, the patient prognostic score for DCIS is associated with the magnitude of improvement in survival offered by RT after BCS, suggesting that decisions for RT could be tailored on the basis of patient factors, tumor biology, and the prognostic score.

The effect of Paget disease on axillary lymph node metastases and survival in invasive ductal carcinoma.

BACKGROUND: The objective of this study was to examine the effect of Paget disease (PD) on axillary lymph node metastases and survival in patients who had concomitant invasive ductal carcinoma (PD-IDC). METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify women who were diagnosed with PD-IDC from 2000 to 2011, comparing baseline demographic and tumor characteristics with those who were diagnosed with IDC alone during the same period. Multivariable logistic regression was used to examine the association of PD-IDC with axillary lymph node metastasis, and breast cancer-specific survival and overall survival were compared between the PD-IDC and IDC groups using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: The study cohort included 1102 patients with PD-IDC and 302,242 controls with IDC alone. PD-IDC tumors were more likely to be centrally located (26.9% vs 5.5%; P < .001), high grade (63.5% vs 40.3%; P < .001), >2 cm in greatest dimension (47.1% vs 35.7%; P < .001), and estrogen/progesterone receptor-negative (45.2% vs 22.1%; P < .001). In adjusted analyses, patients with PD-IDC had higher odds of axillary lymph node metastasis (odds ratio, 1.83; P < .001). The unadjusted 10-year breast cancer-specific and overall survival rates were lower for the PD-IDC group compared with the IDC-alone group, although, after adjusting for disease stage, tumor characteristics, and local therapy, no significant differences in mortality risk were observed between the 2 groups (hazard ratio, 0.91; P = .24). CONCLUSIONS: PD-IDC is associated with an increased risk of axillary lymph node metastasis, but not with inferior survival, compared with IDC alone after adjustment for other disease factors.

Modern Trends in the Surgical Management of Paget's Disease.

PURPOSE: We examined the incidence and modern national trends in the management of Paget's disease (PD), including the use of breast-conserving surgery (BCS), mastectomy, axillary surgery, and receipt of radiotherapy. METHODS: Using surveillance, epidemiology and end results (SEER) data, we identified 2631 patients diagnosed with PD during 2000-2011. Of these patients, 185 (7%) had PD of the nipple only, 953 (36.2%) had PD with ductal carcinoma in situ (PD-DCIS), and 1493 (56.7%) had PD with invasive ductal carcinoma (PD-IDC). Trends in age-adjusted incidence, primary surgery, sentinel lymph node biopsy (SLNB), and axillary lymph node dissection were examined. Multivariable logistic regression was used to evaluate factors associated with receipt of BCS and radiotherapy. RESULTS: A decrease in the age-adjusted incidence of PD occurred from 2000 to 2011 (-4.3% per year, p < 0.05). The overall rates of mastectomy in the PD only, PD-DCIS, and PD-IDC groups were 47, 69, and 88.9%, respectively. Only in the PD-IDC group did the proportion of patients undergoing BCS increase significantly, from 8.5% in 2000 to 15.7% in 2011 (p = 0.01). Of those who underwent axillary surgery, the proportion of patients undergoing SLNB increased from 2000 to 2011. In adjusted analyses, Paget's subgroup, older age, central tumor location, low/intermediate grade, tumor size <2.0 cm, SEER region, and year of diagnosis after 2006 were significantly associated with receipt of BCS. CONCLUSIONS: The incidence of Paget's disease has decreased over time while modern trends in local therapy suggest that BCS, SLNB, and adjuvant radiotherapy remain underutilized.

Survival Benefit of Breast Surgery for Low-Grade Ductal Carcinoma In Situ: A Population-Based Cohort Study.

IMPORTANCE: While the prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially following the introduction of breast-screening methods, the clinical significance of early detection and treatment for DCIS remains unclear. OBJECTIVE: To investigate the survival benefit of breast surgery for low-grade DCIS. DESIGN, SETTING, AND PARTICIPANTS: A retrospective longitudinal cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from October 9, 2014, to January 15, 2015, at the Dana-Farber/Brigham Women's Cancer Center. Between 1988 and 2011, 57,222 eligible cases of DCIS with known nuclear grade and surgery status were identified. EXPOSURES: Patients were divided into surgery and nonsurgery groups. MAIN OUTCOMES AND MEASURES: Propensity score weighting was used to balance patient backgrounds between groups. A log-rank test and multivariable Cox proportional hazards model was used to assess factors related to overall and breast cancer-specific survival. RESULTS: Of 57,222 cases of DCIS identified in this study, 1169 cases (2.0%) were managed without surgery and 56,053 cases (98.0%) were managed with surgery. With a median follow-up of 72 months from diagnosis, there were 576 breast cancer-specific deaths (1.0%). The weighted 10-year breast cancer-specific survival was 93.4% for the nonsurgery group and 98.5% for the surgery group (log-rank test, P < .001). The degree of survival benefit among those managed surgically differed according to nuclear grade (P = .003). For low-grade DCIS, the weighted 10-year breast cancer-specific survival of the nonsurgery group was 98.8% and that of the surgery group was 98.6% (P = .95). Multivariable analysis showed there was no significant difference in the weighted hazard ratios of breast cancer-specific survival between the surgery and nonsurgery groups for low-grade DCIS. The weighted hazard ratios of intermediate- and high-grade DCIS were significantly different (low grade: hazard ratio, 0.85; 95% CI, 0.21-3.52; intermediate grade: hazard ratio, 0.23; 95% CI, 0.14-0.42; and high grade: hazard ratio, 0.15; 95% CI, 0.11-0.23) and similar results were seen for overall survival. CONCLUSIONS AND RELEVANCE: The survival benefit of performing breast surgery for low-grade DCIS was lower than that for intermediate- or high-grade DCIS. A prospective clinical trial is warranted to investigate the feasibility of active surveillance for the management of low-grade DCIS.

Pilot study to evaluate feasibility of image-guided breast-conserving therapy in the advanced multimodal image-guided operating (AMIGO) suite.

BACKGROUND: The rate of reexcision in breast-conserving surgery remains high, leading to delay in initiation of adjuvant therapy, increased cost, increased complications, and negative psychological impact to the patient.1 (-) 3 We initiated a phase 1 clinical trial to determine the feasibility of the use of intraoperative magnetic resonance imaging (MRI) to assess margins in the advanced multimodal image-guided operating (AMIGO) suite. METHODS: All patients received contrast-enhanced three-dimensional MRI while under general anesthesia in the supine position, followed by standard BCT with or without wire guidance and sentinel node biopsy. Additional margin reexcision was performed of suspicious margins and correlated to final pathology (Fig. 1). Feasibility was assessed via two components: demonstration of safety and sterility and acceptable duration of the operation and imaging; and adequacy of intraoperative MRI imaging for interpretation and its comparison to final pathology. Fig. 1 Schema of AMIGO trial RESULTS: Eight patients (mean age 48.5 years), 4 with stage I breast cancer and 4 with stage II breast cancer, were recruited. All patients underwent successful BCT in the AMIGO suite with no AMIGO-specific complications or break in sterility during surgery. The mean operative time was 113 min (range 93-146 min). CONCLUSIONS: Our experience with AMIGO suggests that it is feasible to use intraoperative MRI imaging to evaluate margin assessment in real time. Further research is required to identify modalities that will lead to a reduction in reexcision in breast cancer therapy.

Extended therapy with letrozole and ovarian suppression in premenopausal patients with breast cancer after tamoxifen.

INTRODUCTION: In premenopausal women with breast cancer, standard adjuvant endocrine therapy has been 5 years of tamoxifen. This study sought to investigate the safety and feasibility of treating patients who remain premenopausal after adjuvant tamoxifen with gonadotropin-releasing hormone agonist (GnRH-a) concurrent with an aromatase inhibitor, mimicking the strategy that has proven effective in postmenopausal patients. PATIENTS AND METHODS: This phase II single-arm clinical trial aimed to enroll 50 premenopausal women who had completed > 4.5 years of adjuvant tamoxifen for a 2-year course of leuprolide (7.5 mg intramuscularly monthly or 22.5 mg intramuscularly every 3 months) and letrozole (2.5 mg orally daily). Zoledronic acid (4 mg intravenously every 6 months) was offered optionally to help prevent bone loss. RESULTS: Despite aggressive recruitment strategies at the 3 participating sites (including Dana-Farber Cancer Institute), poor accrual over 3.5 years ultimately led to early study closure after only 16 patients began therapy. Of the 16, 4 stopped treatment before 1 year, owing to toxicity; 5 completed 2 years of protocol-directed therapy; and 7 remained on treatment as of September 1, 2013, for an average of 53.5 weeks (SD, 17.2 weeks). Hot flashes, vaginal dryness, and pain were common toxicities. CONCLUSION: Extended therapy with GnRH-a and an aromatase inhibitor (plus optional bisphosphonate) is associated with substantial side effects in premenopausal women who have already completed > 4.5 years of adjuvant tamoxifen. This study's poor accrual suggests that young women may not be highly motivated to pursue lengthier courses of endocrine therapy and that future studies of this approach may be challenging.

Personalized medicine in breast cancer: tamoxifen, endoxifen, and CYP2D6 in clinical practice.

Tamoxifen is metabolized into endoxifen, a potent antagonist of the estrogen receptor, in part through cytochrome p450 (CYP) 2D6. Genotypic variation in CYP2D6 affects endoxifen levels, and some have argued that patients who do not efficiently metabolize tamoxifen might wish to consider alternative hormonal treatments. This study evaluated an algorithm in which endoxifen levels and CYP2D6 genotypes were used to make hormonal therapy recommendations for patients on adjuvant tamoxifen for breast cancer. Patients with stage I-III breast cancer who had been taking adjuvant tamoxifen for 8-56 weeks were eligible. At enrollment, baseline whole blood and serum were sent for genotyping by Amplichip and endoxifen measurement, respectively, and endoxifen levels were also measured 3 weeks later. Results were returned to oncologists along with an algorithm-generated treatment recommendation. The algorithm recommended that participants with poor metabolizer genotype and/or baseline endoxifen level <6 ng/mL consider alternative endocrine therapy. A medical record review evaluated actual treatment decisions. Of 99 patients on study, 18 (18 %) had findings that triggered algorithm-based recommendations to consider a change in endocrine therapy due to endoxifen <6 ng/mL (all 18 patients) and/or poor metabolizer CYP2D6 genotype (2 of the 18). Endoxifen levels were ≥6 ng/mL in four of them 3 weeks later. Seven (39 % of 18) switched to a different treatment (one based on toxicity, not the algorithm). Hot flash burden was not found to be significantly associated with endoxifen <6 ng/mL or genotype. Prospective testing of tamoxifen metabolism as gauged by CYP2D6 genotype and serum endoxifen levels is feasible. Future studies of tamoxifen metabolism and efficacy should consider including measurement of serial endoxifen levels. Although clinical evidence at present is insufficient to warrant routine CYP2D6 or endoxifen testing, some clinicians and patients did utilize this predefined algorithm to inform clinical decisions regarding optimal adjuvant endocrine therapy.

Estimation of tamoxifen metabolite concentrations in the blood of breast cancer patients through CYP2D6 genotype activity score.

Tamoxifen, a prodrug used for adjuvant breast cancer therapy, requires conversion to the active metabolite endoxifen through CYP 2D6. We aimed to construct an algorithm to predict endoxifen concentrations based on a patient's CYP 2D6 genotype, demographic factors, and co-medication use. Eighty-eight women enrolled in the UCSF TamGen II study and 81 women enrolled in a prospective study at Dana-Farber Cancer Institute were included in this analysis. All the women had been on tamoxifen for at least 3 months before blood collection. Demographic information included the patient's age, race/ethnicity, body mass index (where available), and self-reported and measured medications and herbals that affect 2D6 activity. DNA was extracted and genotyped for 2D6 (Amplichip, Roche Diagnostics). An activity score was calculated based on genotypes and adjusted for use of medications known to inhibit 2D6. Serum was tested for tamoxifen and metabolite concentrations and for the presence of drugs by liquid chromatography/mass spectrometry. Univariate and multivariate regression analysis were computed for age, body mass index, ethnicity, and adjusted activity score to predict tamoxifen metabolite concentrations in the training data-set of UCSF patients, and the resulting algorithm was validated in the Dana-Farber patients. For the training set, the correlation coefficient (r2) for log endoxifen and N-desmethyltamoxifen:endoxifen ratio to activity score, age, and race, were 0.520 and 0.659, respectively; 0.324 and 0.567 for the validation; and 0.396 and 0.615 for both the datasets combined. An algorithm that incorporates genotype and demographic variables can be used to predict endoxifen concentrations for women on tamoxifen therapy. If endoxifen levels are confirmed to be predictive of tamoxifen benefit, then this algorithm may be helpful to determine which women warrant endoxifen testing.