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Background: Postmastectomy breast reconstruction in patients with a history of breast-conserving surgery (BCS) and radiotherapy is challenging, with a paucity of literature on the outcomes of different breast reconstructive techniques. The authors hypothesized that implant-based breast reconstruction (IBR) would be associated with higher complication rates compared to either IBR combined with latissimus dorsi (LD) or free flap breast reconstruction (FFBR)., Methods: The authors conducted a retrospective review of patients who underwent mastectomy with a history of BCS and radiotherapy between January of 2000 and March of 2016. Surgical and patient-reported outcomes (BREAST-Q) were compared between IBR versus IBR/LD versus FFBR., Results: The authors identified 9473 patients who underwent BCS and radiotherapy. Ninety-nine patients (105 reconstructions) met the authors' inclusion criteria, 29% ( n = 30) of whom underwent IBR, 26% ( n = 27) of whom underwent IBR/LD, and 46% ( n = 48) of whom underwent FFBR. The overall complication rate was not significantly different between the three groups (50% in IBR versus 41% in IBR/LD versus 44% in FFBR; P = 0.77), whereas reconstruction failures were significantly lower in the FFBR group (33% in IBR versus 19% in IBR/LD versus 0% in FFBR; P < 0.0001). The time between the receipt of radiotherapy and reconstruction was not a significant predictor of overall complications and reconstruction failure. No significant differences were identified between the three study cohorts in any of the three studied BREAST-Q domains., Conclusions: In patients with prior BCS and radiotherapy, FFBR was associated with lower probability of reconstruction failure compared to IBR but no significant difference in overall and major complication rates. The addition of LD flap to IBR did not translate into lower complication rates but may result in decreased reconstruction failures., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background: "Old" randomized controlled trials established breast conserving therapy (BCT) and total mastectomy (TM) equivalence for treating early breast cancer, whereas recent literature report improved survival with BCT. To reconcile this, we performed a simulation study and re-analyzed B-06 trial data. Methods: We estimated the distributions for overall survival (OS), cumulative incidence functions for breast-cancer-specific death (BCSD) and other causes-specific death (OCSD) by BCT and TM. The restricted mean survival time (RMST) difference and hazard ratio between the two arms were estimated. Given the estimated distributions, we simulated cause-specific death times from each arm, evaluating the power to test treatment difference in OS, BCSD, and OCSD with different sample sizes, follow-up times, and a modified setting by simulating BCT-arm OCSD times from the distribution of patients not receiving radiation. Results: With 200 months follow-up, the average BCT-over-TM gain measured by RMST was 3.7 months for OS and 4.5 months for BCSD. Increasing the trial size to 5,000 per arm, there is a 79.2% chance to detect the OS benefit with RMST and 92.4% for BCSD. A nonproportional increase of OCSD in BCT compared to TM was observed after 144 months, and particularly after 200 months post treatments. When OCSD times of BCT were simulated using patients not receiving radiation, the estimated OS gain increased to 4.4 months, and the power increased to 92.2%. Conclusions: The late excess other-cause-death, likely due to radiation, in the BCT arm and sample size constraints limited the power to report BCT superiority. Given radiation delivered in the era of B-06 trial, BCT and TM remain largely equivalent., Competing Interests: Competing Interests: SFS received grant from Emerson Collective Foundation, and contracted research agreements from Alpha Tau, Exact Science, TAE Life Sciences and Artios Pharm. Other authors have no conflicts of interest to disclose., (© The author(s).)

Background: Patients with unilateral breast cancer carrying pathogenic variants in BRCA1/2 have the option to undergo contralateral prophylactic mastectomy (CPM). However, differences in CPM use and survival outcomes following CPM are poorly understood in this high-risk population, in part due to a lack of data from contemporary clinical cohorts. The objective of this study was to evaluate post-CPM overall survival (OS) and related racial/ethnic differences in a contemporary clinical cohort., Methods: We retrospectively reviewed the medical records of women with a personal history of unilateral breast cancer carrying pathogenic variants in BRCA1/2 who were diagnosed between 1996 and 2012. Genetic test results, self-reported demographic characteristics, and clinical factors were abstracted from electronic medical records., Results: Of 144 BRCA-positive patients, the majority were White (79.2%, n  = 114). Overall, 56.1% ( n  = 81) of all BRCA1/2 carriers chose to undergo CPM, with no racial/ethnic difference in CPM election ( p  = 0.78). Of 81 patients who underwent CPM, there is strong evidence of a difference in survival between the racial/ethnic groups, with White patients having the highest OS compared to non-White patients ( p  = 0.001). Of the 63 patients who did not undergo CPM, there is no racial/ethnic difference in overall survival ( p  = 0.61). In multivariable cox regression, adjusted for demographic and clinical characteristics, OS was significantly lower among non-Whites than in Whites (HR = 0.39, p  = 0.04)., Conclusions: Evaluation of a contemporary clinical cohort of BRCA-positive women with unilateral breast cancer showed no racial/ethnic difference in CPM use, but there was a significant difference in post-CPM overall survival., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Sukh Makhnoon et al.)

Objective: To review breast cancer incidence in women with ADH diagnosed by CNB and managed nonoperatively., Background: ADH found on CNB is associated with an upgrade to carcinoma in 10%-50% of women, thus surgical excision remains the standard of care. Safety of nonoperative management is unknown., Methods: ADH patients diagnosed between January 2004 and October 2018 were identified. Subsequent breast cancer events were compared between those who were excised and those who met predetermined criteria of low risk and were thus observed. Subsequent breast cancer events were classified as index site event if identified in the same quadrant as prior ADH. Multivariable logistic regression models were used to assess potential predictors of subsequent breast cancer events., Results: Four hundred seventy-eight women with 483 ADH lesions were identified; 309 were observed and 174 underwent excision. Median follow-up was 5.2 years. Prior breast cancer history was the only factor associated with subsequent breast cancer risk (odds ratio 2.25, 95% confidence interval 1.04-4.87). After excluding patients with a breast cancer history, there was no association of age, race, chemoprevention, or surgical excision of ADH with future cancer risk. 21/387 patients without a breast cancer history developed a subsequent cancer; 10 (7.3%) in the surgical group and 11 (4.4%) in the observed ( P = 0.2). Two cancers were identified at the index site in the surgery group (2/137, 1.5%) and three in those observed (3/250, 1.2%)., Conclusions: Observation, rather than surgical excision, is safe in select women with ADH. National guidelines should consider observation for this select group of patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

To determine whether Medicaid expansion under the 2010 Affordable Care Act affected rates of breast cancer surgery., Background: Data regarding the impact of Medicaid expansion on access to surgical treatment of breast cancer are limited., Methods: Patients in the National Cancer Database diagnosed with non-metastatic breast cancer between January 1, 2010 and December 31, 2017 and residing in a state that expanded Medicaid in January 2014 or in a state that opted out of expansion were included. A quasi-experimental, difference-in-differences (DID) approach was used to assess rate of omission of surgical treatment., Results: Of 624,237 patients diagnosed with invasive breast cancer, 24,728 (4%) patients did not undergo surgical treatment. Overall, no significant differences in rates of omission of surgery over time were seen based on Medicaid expansion status. Significant findings were noted based on patient residential location. In rural areas, Medicaid expansion was associated with lower rates of omission of surgery (adjusted DID -2.47%, 95% confidence interval [CI] -4.01% to -0.94%; P = 0.002). In urban area, rates of omission of surgery increased over time for both groups, but the relative increase was lower in expansion states (adjusted DID -0.72%, 95% CI -1.25% to -0.20%; P = 0.007). In metro areas, changes in rates of surgery over time were comparable across expansion and non-expansion states (adjusted DID -0.08%, 95% CI -0.32% to 0.16%; P = 0.512)., Conclusions: Medicaid expansion had no measurable effect on the receipt of surgery for breast cancer in the overall cohort. Medicaid expansion was associated with higher rates of surgery in rural areas, representing the minority of the population., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To evaluate prediction of response and event-free survival (EFS) following neoadjuvant endocrine therapy by SET2,3 index of nonproliferation gene expression related to estrogen and progesterone receptors adjusted for baseline prognosis., Experimental Design: A correlative study was conducted of SET2,3 measured from gene expression profiles of diagnostic tumor (Agilent microarrays) in 379 women with cStage II-III breast cancer from the American College of Surgeons Oncology Group Z1031 neoadjuvant aromatase inhibitor trial SET2,3 was dichotomized using the previously published cutoff. Fisher exact test was used to assess the association between SET2,3 and low proliferation at week 2-4 [Ki67 ≤ 10% or complete cell-cycle arrest (CCCA; Ki67 ≤ 2.7%)] and PEPI-0 rate in cohort B, and the association between SET2,3 and ypStage 0/I in all patients. Cox models were used to assess EFS with respect to SET2,3 excluding cohort B patients who switched to chemotherapy., Results: Patients with high SET2,3 had higher rate of pharmacodynamic response than patients with low SET2,3 (Ki67 ≤ 10% in 88.2% vs. 56.9%, P < 0.0001; CCCA in 50.0% vs. 26.2%, P = 0.0054), but rate of ypStage 0/I (24.0% vs. 20.4%, P = 0.4580) or PEPI = 0 (28.4% vs. 20.6%, P = 0.3419) was not different. Patients with high SET2,3 had longer EFS than patients with low SET2,3 (HR, 0.52, 95% confidence interval: 0.34-0.80; P = 0.0026)., Conclusions: This exploratory analysis of Z1031 data demonstrated a higher rate of pharmacodynamic suppression of proliferation and longer EFS in high SET2,3 disease relative to low SET2,3 disease. The ypStage 0/I rate and PEPI = 0 rate were similar with respect to SET2,3., (©2022 The Authors; Published by the American Association for Cancer Research.)

In the therapeutic domain, targeted therapies have been shown to be generally more effective when given to patients with tumors that harbor the targeted aberration. This principle has not been tested in cancer prevention despite evidence that molecular heterogeneity accompanies the multi-step progression to invasive disease. We hypothesized that efficacy of agents targeting the precancerous state varies based on timing of the treatment relative to the underlying molecular changes. MCF10A cell line-based model of the multi-step progression to TNBC was used. Global proteomic patterns were obtained and growth-inhibitory effects of selected agents were correlated with the underlying molecular stage of progression. These analyses revealed that most protein alterations were acquired in the normal-to-atypia (preneoplasia) transition, with only handful aberrations acquired hereafter. The efficacy of small molecule inhibitors of the AKT/MEK pathway was associated with the underlying pathway levels. Similarly, fluvastatin was more effective in inhibiting cell proliferation earlier in the progression model. However, the nonspecific inhibitors, aspirin and metformin, were equally ineffective in inhibiting proliferation across the progression model. Our data provides proof-of-principle that in the prevention domain, treatment with agents developed to target specific pathways, will need to consider the molecular heterogeneity of the precancerous breast in order to achieve maximum efficacy., (© 2022. The Author(s).)

Purpose of Review: Individuals carrying germline mutations in BRCA1/2 have unique psychosocial and educational needs that must be met to ensure informed clinical decision-making. In this review, we highlight the strategies used in clinical practice to support patients' needs as well as currently available pre- and post-disclosure support interventions., Recent Findings: Clinical risk communication is complicated by the uncertainty associated with gene penetrance, inconclusive results, variable effectiveness of surgical and screening interventions, and inadequate awareness of clinical genetics. Interventions to support patients' psychosocial needs, and strategies for effective and scalable clinical risk communication are in routine use and largely effective at meeting patients' needs. Research is underway to develop newer supportive resources; however, the inadequate representation of all mutation carriers persists. Effective clinical risk communication strategies, decision support aids, written educational materials, and supportive psychosocial tools can together have a large impact on meeting BRCA carriers' supportive needs., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Although targeting of the cholesterol pathway by statins prevents breast cancer development in mouse models, efficacy is not absolute. Therefore, the goal of this study is to investigate if the upregulation in the cholesterol biosynthesis pathway genes associates with response to statin chemoprevention and may potentially be used as response biomarkers., Methods: Expression of cholesterol biosynthesis pathway genes was initially derived from the RNA sequencing of MCF10A cell line- based breast cancer progression model system and subsequently validated by quantitative PCR assay. Response to fluvastatin was assessed in vitro using the MCF10A cell line model system, including a statin resistant cell line that was generated (MCF10.AT1-R), and measured using colony forming assays. In vivo efficacy of statin for chemoprevention was assessed in the SV40C3 TAg mouse model. Mammary tumors were identified by histologic analysis of the mammary glands. Mammary glands without histologic evidence of high-grade lesions (in situ and/or invasive carcinoma) were considered responsive to statin treatment., Results: We found more than 70% of a published multi-gene fluvastatin resistance signature to be significantly upregulated during breast cancer progression and inversely correlated with statin inhibition of cellular growth and proliferation. This inherent statin resistance gene signature was also largely shared with the signature of acquired resistance to fluvastatin in MCF10.AT1-R cell line model of acquired statin resistance. These inherent resistance genes and genes exclusive to acquired statin resistance map to steroid-, and terpenoid backbone- biosynthesis pathway. We found upregulation of ~ 80% of cholesterol biosynthesis pathway genes in the tumor bearing mammary glands of SV40 C3TAg transgenic mouse model of TNBC, suggesting the involvement of cholesterol biosynthesis pathway in resistance to statin chemoprevention in vivo. A panel of 13-genes from the pathway significantly associated with response to statin treatment, as did the expression level of HMGCR alone in a mouse model of breast cancer suggesting their utility to predict the efficacy of statin chemoprevention., Conclusions: High basal level, or restorative upregulation, in the cholesterol biosynthesis pathway genes appear to be strongly associated with resistance to statin chemoprevention for breast cancer and may serve as a biomarker to tailor statin treatment to individuals who are most likely to benefit., (© 2022. The Author(s).)

Purpose: Multigene panel testing has increased the detection of germline mutations in patients with breast cancer. The implications of using radiation therapy (RT) to treat patients with pathogenic variant (PV) mutations are not well understood and have been studied mostly in women with only BRCA1 or BRCA2 PVs. We analyzed oncologic outcomes and toxicity after adjuvant RT in a contemporary, diverse cohort of patients with breast cancer who underwent genetic panel testing., Methods and Materials: We retrospectively reviewed the records of 286 women with clinical stage I-III breast cancer diagnosed from 1995 to 2017 who underwent surgery, breast or chest wall RT with or without regional nodal irradiation, multigene panel testing, and evaluation at a large cancer center's genetic screening program. We evaluated rates of overall survival, locoregional recurrence, disease-specific death, and radiation-related toxicities in 3 groups: BRCA1/2 PV carriers, non-BRCA1/2 PV carriers, and patients without PV mutations., Results: PVs were detected in 25.2% of the cohort (12.6% BRCA1/2 and 12.6% non-BRCA1/2). The most commonly detected non-BRCA1/2 mutated genes were ATM, CHEK2, PALB2, CDH1, TP53, and PTEN. The median follow-up time for the entire cohort was 4.4 years (95% confidence interval, 3.8-4.9 years). No differences were found in overall survival, locoregional recurrence, or disease-specific death between groups (P > .1 for all). Acute and late toxicities were comparable across groups., Conclusion: Oncologic and toxicity outcomes after RT in women with PV germline mutations detected by multigene pane testing are similar to those in patients without detectable mutations, supporting the use of adjuvant RT as a standard of care when indicated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: BRCA1/2 pathogenic variant (PV) mutations confer radiation sensitivity preclinically, but there are limited data regarding breast cancer outcomes after radiation therapy (RT) among patients with documented BRCA1/2 PV mutations versus no PV mutations., Methods and Materials: This retrospective cohort study included women with clinical stage I-III breast cancer who received definitive surgery and RT and underwent BRCA1/2 genetic evaluation at the The University of Texas MD Anderson Cancer Center. Rates of locoregional recurrence (LRR), disease-specific death (DSD), toxicities, and second cancers were compared by BRCA1/2 PV status., Results: Of the 2213 women who underwent BRCA1/2 testing, 63% self-reported their race as White, 13.6% as Black/African American, 17.6% as Hispanic, and 5.8% as Asian/American Indian/Alaska Native; 124 had BRCA1 and 100 had BRCA2 mutations; and 1394 (63%) received regional nodal RT. The median follow-up time for all patients was 7.4 years (95% confidence interval [CI], 7.1-7.7 years). No differences were found between the groups with and without BRCA1/2 PV mutations in 10-year cumulative incidences of LRR (with mutations: 11.6% [95% CI, 7.0%-17.6%]; without mutations: 6.6% [95% CI, 5.3%-8.0%]; P = .466) and DSD (with mutations: 12.3% [95% CI, 8.0%-17.7%]; without mutations: 13.8% [95% CI, 12.0%-15.8%]; P = .716). On multivariable analysis, BRCA1/2 status was not associated with LRR or DSD, but Black/African American patients (P = .036) and Asians/American Indians/Alaska Native patients (P = .002) were at higher risk of LRR compared with White patients, and Black/African American patients were at higher risk of DSD versus White patients (P = .004). No in-field, nonbreast second cancers were observed in the BRCA1/2 PV group. Rates of acute and late grade ≥3 radiation-related toxicity in the BCRA1/2 PV group were 5.4% (n = 12) and 0.4% (n = 1), respectively., Conclusions: Oncologic outcomes in a diverse cohort of patients with breast cancer who had a germline BRCA1/2 PV mutation and were treated with RT were similar to those of patients with no mutation, supporting the use of RT according to standard indications in patients with a germline BRCA1/2 PV mutation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The early COVID-19 pandemic rapidly transformed healthcare and medical education. We sought to evaluate the professional and personal impact of the pandemic on 2019-2020 Breast Surgical Oncology (BSO) fellows in Society of Surgical Oncology approved programs to capture the experience and direct future changes., Methods: From July 15, 2020 to August 4, 2020 a survey was administered to the American Society of Breast Surgeons' fellow members. The survey assessed the impact of the pandemic on clinical experience, education/research opportunities, personal health/well-being, and future career. Responses were collected and aggregated to quantify the collective experience of respondents., Results: Twenty-eight of fifty-seven (54%) eligible fellows responded. Twenty-one (75%) indicated the clinical experience changed. Twenty-seven (96%) reported less time spent caring for ambulatory breast patients and sixteen (57%) reported the same/more time spent in the operating room. Fourteen (50%) stated their future job was impacted and eight (29%) delayed general surgery board examinations. Stress was increased in 26 (93%). Personal health was unaffected in 20 (71%), and 3 (10%) quarantined for COVID-19 exposure/infection., Conclusion: The COVID-19 pandemic altered the clinical experience of BSO fellows; however, the operative experience was generally unaffected. The creation of frameworks and support mechanisms to mitigate potential challenges for fellows and fellowship programs in the ongoing pandemic and other times of national crisis should be considered., (© 2021 Wiley Periodicals LLC.)

Background: Nearly one-third of patients with inflammatory breast cancer (IBC) present with de novo stage IV disease. There are limited data on frequency and clinical outcomes of contralateral axillary metastasis (CAM) in IBC with no consensus diagnostic and treatment guidelines., Patients and Methods: Frequency of synchronous CAM was calculated in unilateral IBC patients at a single center (10/2004-6/2019). Clinicopathologic variables, diagnostic evaluation, treatment received, and overall survival (OS) were assessed and compared., Results: Of 588 unilateral IBC patients, 49 (8.3%) had synchronous CAM. Of these, 32 (65.3%) also presented with metastatic disease at another distant site. CAM was not associated with age, tumor laterality, breast cancer subtype, grade, or cN stage (p > 0.05). The sensitivity/specificity to detect CAM was as follows: mammography (18.2%/99.2%), ultrasound (92.3%/95.5%), PET (90.1/99.1%), and MRI (76.0%/98.6%). Following systemic therapy, 22 patients had contralateral axillary surgery, and 18 received adjuvant contralateral nodal radiation. On multivariable analysis including tumor receptor subtypes, patients with stage IV-isolated CAM has statistically similar survival to stage III patients (HR 1.37, 95% CI 0.70-2.69, p = 0.36). Patients with Stage IV non-CAM (HR 2.18, 95% CI 1.66-2.85, p < 0.001) and stage IV-CAM plus other distant metastasis (HR 2.57, 95% CI 1.59-4.16, p < 0.001) had higher risk of death (reference: stage III disease)., Conclusions: CAM in IBC was diagnosed in 8.3% of patients at presentation and was best identified by ultrasound and PET. We recommend routine contralateral axillary ultrasound as part of staging for all IBC patients. Diagnosis of CAM is a key first step toward much-needed prospective clinical trials evaluating management and outcomes of CAM in IBC., (© 2021. Society of Surgical Oncology.)

Background: Targeted axillary dissection (TAD) involves locating and removing both clipped nodes and sentinel nodes for assessment of the axillary response to neoadjuvant chemotherapy (NAC) by clinically node-positive breast cancer patients. Initial reports described radioactive seeds used for localization, which makes the technique difficult to implement in some settings. This trial was performed to determine whether magnetic seeds can be used to locate clipped axillary lymph nodes for removal., Methods: This prospective registry trial enrolled patients who had biopsy-proven node-positive disease with a clip placed in the node and treatment with NAC. A magnetic seed was placed under ultrasound guidance in the clipped node after NAC. All the patients underwent TAD., Results: Magnetic seeds were placed in 50 patients by 17 breast radiologists. All the patients had successful seed placement at the first attempt (mean time for localization was 6.1 min; range 1-30 min). The final position of the magnetic seed was within the node (n = 44, 88%), in the cortex (n = 3, 6%), less than 3 mm from the node (n = 2, 4%), or by the clip when the node could not be adequately visualized (n = 1, 2%). The magnetic seed was retrieved at surgery from all the patients. In 49 (98%) of the 50 cases, the clip and magnetic seed were retrieved from the same node. Surgeons rated the transcutaneous and intraoperative localization as easy for 43 (86%) of the 50 cases. No device-related adverse events occurred., Conclusions: Localization and selective removal of clipped nodes can be accomplished safely and effectively using magnetic seeds.

Background: Data are lacking about the benefit of adjuvant endocrine therapy (ET) in older patients with multiple comorbidities. The authors sought to determine the effect of ET on the survival of older patients who had multiple comorbidities and estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, pathologic node-negative (pN0) breast cancer., Methods: Women aged ≥70 years in the National Cancer Database (2010-2014) with Charlson/Deyo comorbidity scores of 2 or 3 who had pathologic tumor (pT1)-pT3/pN0, ER-positive/HER2-negative breast cancer were divided into 2 cohorts: adjuvant ET and no ET. Propensity scores were used to match patients based on age, comorbidity score, facility type, pT classification, chemotherapy, surgery, and radiation therapy. A Cox proportional hazards model was used to estimate the effect of ET on overall survival (OS)., Results: In the nonmatched cohort (n = 3716), 72.8% of patients received ET (n = 2705), and 27.2% did not (n = 1011). The patients who received ET were younger (mean age, 76 vs 79 years; P < .001) and had higher rates of breast conservation compared with those who did not receive ET (lumpectomy plus radiation: 43.4% vs 23.8%, respectively; P < .001). In the matched cohort (n = 1972), the median OS was higher in the ET group (79.2 vs 67.7 months; P < .0001). In the adjusted analysis, ET was associated with improved survival (hazard ratio, 0.70; 95% CI, 0.59-0.83)., Conclusions: In older patients who have pN0, ER-positive/HER2-negative breast cancer with comorbidities, adjuvant ET was associated with improved OS, which may have been overestimated given the confounders inherent in observational studies. To optimize outcomes in these patients, current standard recommendations should be considered stage-for-stage based on life expectancy and the level of tolerance to treatment., (© 2021 American Cancer Society.)

Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and toxicity limits use of these agents. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects. This study evaluates the effect of 1-year of vitamin D supplementation on mammographic density (MD), a biomarker of breast cancer risk in a multicenter randomized controlled trial. Premenopausal women with ≥25% MD and no history of cancer were randomly assigned to 2,000 international units (IU) of vitamin D or placebo orally daily for 1 year. Change in percent MD was evaluated using Cumulus software after all participants completed treatment. Three hundred women enrolled between January 2011 and December 2013 with a mean age of 43 and diverse ethnicity [14% Hispanic, 12% African American (AA)]. Supplementation significantly increased vitamin D levels compared with placebo (14.5 ng/mL vs. -1.6 ng/mL; P < 0.0001) with all participants on the vitamin D arm achieving vitamin D sufficiency at 12 months. Vitamin D was safe and well tolerated. After adjustment for baseline MD, the mean between-arm difference (vitamin D vs. placebo) at 1 year was -0.75 (-0.26, 1.76; P = 0.56). A greater effect was seen for women with ≥50% MD and AA women, although neither reached significance. This randomized controlled trial demonstrated significant improvement in vitamin D levels with 2,000 IU for 1 year, with 100% of supplemented women achieving sufficiency. However, a null effect was seen regarding change in MD for premenopausal women (the primary outcome of the study). PREVENTION RELEVANCE: Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and are underutilized due to toxicity and side effects. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects., (©2021 American Association for Cancer Research.)

Purpose: Primary prevention of hormonally insensitive breast cancers remains an important clinical need and repurposing existing low-toxicity drugs represents a low-cost, efficient strategy for meeting this goal. This study targeted the cholesterol pathway using fluvastatin, a cholesterol-lowering drug, and aspirin, an AMPK activator that acts as a brake in the cholesterol pathway, in a transgenic mouse model of triple-negative breast cancer (TNBC)., Methods: Using SV40C3 TAg mice, the efficacy and mechanism of fluvastatin, aspirin, or both in combination were compared with vehicle alone., Results: Sixteen-weeks of fluvastatin treatment resulted in significant delay in onset of tumors (20 weeks vs. 16.8 weeks in vehicle treatment, p = 0.01) and inhibited tumor incidence and tumor multiplicity by 50% relative to the vehicle control. In animals that developed tumors, fluvastatin treatment inhibited tumor weight by 75% relative to vehicle control. Aspirin alone did not significantly affect tumor latency, tumor incidence or tumor burden compared to vehicle control. Fluvastatin and aspirin in combination delayed the onset of tumors but failed to inhibit tumor incidence and tumor multiplicity. The growth-inhibitory effects of fluvastatin were mediated through increased FAS/FASL mediated apoptotic cell death that was characterized by increased cleaved PARP and driven in part by depletion of an isoprenoid, geranyl geranyl pyrophosphate (GGPP)., Conclusions: In line with NCI's emphasis to repurpose low-toxicity drugs for prevention of cancer, fluvastatin was effective for prevention of TNBC and warrants further clinical testing. Aspirin did not provide chemopreventive benefit.

Purpose: HER2 overexpression and gene amplification are routinely tested by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. In addition, HER2 mRNA expression is also tested by the Oncotype DX assay. Discordance between laboratories among the different assays remains a problem. To improve the routine HER2 reporting, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) updated their guidelines in 2018. Our study will compare concordance of HER2 status by IHC and FISH using ASCO/CAP 2013 and 2018 guidelines with Oncotype DX., Methods: We retrospectively reviewed 657 estrogen receptor positive primary breast cancer cases with available Oncotype DX tests between 2011 and 2018. Medical records were reviewed for HER2 results by IHC, FISH, and Oncotype DX. The HER2 results by different assays and between 2013 and 2018 guidelines were compared., Results: Of the 657 cases, 280 were tested by IHC, FISH, and Oncotype DX. HER2-equivocal cases by IHC 2013 guidelines were all negative (67/67, 100%) by FISH 2018 guidelines and by Oncotype DX. HER2-equivocal cases by FISH 2013 guidelines were all negative (16/16, 100%) by FISH 2018 guidelines, while 15/16 (93.8%) negative and 1/16 (6.2%) equivocal by Oncotype DX. The HER2-equivocal and HER2-negative groups were similar in age, gender, histology, grade, and Ki67 score., Conclusions: HER2 concordance was highest between Oncotype DX (99.6%) and FISH per 2018 guidelines. This suggests that the ASCO/CAP 2018 guidelines improved the accurate stratification of HER2-equivocal cases.

Purpose: A uniform classification framework for neuroendocrine neoplasms (NENs) in all the organ systems has been recently proposed by an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert panel. Based on the new classification system, the NENs of the breast are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). This study is aimed to analysis the prognostic differences between NENs and invasive ductal carcinomas of no special type (IDCs-NST)., Methods: The surveillance, epidemiology, and end results (SEER) database released on November 2018 was used for this study. Between 2003 and 2016, 361 NENs (NET = 239, NEC = 122) of the breast and 491,908 of IDCs-NST were identified. Survival analysis was performed for disease-specific survival (DSS) and overall survival (OS)., Results: The 5-year DSS of NET, NEC, and IDC-NST was 63.39%, 46.00%, and 89.17%, respectively. And the 5-year OS of NET, NEC, and IDC-NST was 55.66%, 38.87%, and 83.17%, respectively. Within the same clinical stage or grade, NETs and NECs of the breast had worse DSS and OS than corresponding stage or grade IDCs-NST (all P < 0.050). In univariate and multivariate survival analysis, NENs of the breast had significantly worse DSS and OS than IDCs-NST (P < 0.001)., Conclusion: The universal classification framework for NEN allowed us to further refine the breast carcinoma with neuroendocrine differentiation as a unique pathologic and clinical entity, which has worse clinical outcome compared to IDC-NST.

Objective: A prospective, phase IV study was conducted to assess the effectiveness of Magseed to localize breast lesions requiring surgical excision., Background: Since FDA approval in 2016, Magseed has been increasingly used to localize non-palpable lesions due to advantages over wires or radioactive seeds. This is the first prospective, post marketing trial of Magseed., Methods: From 1/2017-2/2018, 107 women with lesions requiring localization were enrolled at a single institution. Primary endpoint was Magseed retrieval rate. Secondary endpoints were adverse events, accuracy of placement, surgery duration and positive margin rate. Clinicians were surveyed for ease of use using a Likert scale. Descriptive statistics and Fisher's exact test were performed to assess univariable associations with positive margins., Results: There were 124 Magseeds placed including one marker in 93 subjects, 2 markers in 11 and 3 markers in 3. The majority of lesions were masses (63%) followed by calcifications (24%). All 124 Magseeds were placed within 10mm of the target lesion and surgically retrieved with median operative time of 15min (range 4-47). No device-related adverse events occurred. Of the 98 malignant lesions, 9 had positive margins and 7 of them underwent a second surgery for additional margins. On univariable analysis, age ≤ 50 (25.0% vs 6.4%, p =0.04), lesion histology ( p = 0.03), and pathologic T-stage ( p = 0.04) were significantly associated with positive margins. Clinicians rated the Magseed very or fairly easy to use in most cases., Conclusions: The Magseed system for localization of non-palpable lesions was effective and safe; all markers were successfully retrieved with margin-negative resections in 91%. This study supports use of Magseed for localization of breast lesions.

Background: Modified radical mastectomy (MRM), which includes axillary dissection, is the standard of care for inflammatory breast cancer (IBC). While more limited axillary staging after neoadjuvant chemotherapy (NAC) in clinically node-positive non-IBC has been increasingly adopted, the impact of these techniques in IBC is not clear. To inform patient selection for further study of limited axillary surgery, we aimed to describe the frequency and factors associated with pathological node-negativity (ypN0) in IBC., Methods: Patients with IBC who received NAC and MRM were identified from a prospective institutional database (2004-2019). Binary logistic regression analyses were conducted to identify factors associated with ypN0., Results: Of 453 patients, 189 (41.7%) had a post-NAC clinical nodal stage (ycN stage) of N0 (ycN1: 150, 33.1%; ycN2: 4, 0.9%; ycN3: 47, 10.4%; unknown: 63, 13.9%); 156 (34%) were ypN0. On multivariable analysis, higher tumor grade was not associated with ypN0 (odds ratio [OR] 1.59, 95% confidence interval [CI] 0.90-2.81, p =0.11). Compared with hormone receptor (HR)-negative/human epidermal growth factor receptor 2 (HER2)-negative tumors (n =113, 24.9%), HR-positive/HER2-negative tumors (n =169, 37.3%) had a trend toward less ypN0 (OR 0.55, 95% CI 0.29-1.02, p =0.06); HR-positive/HER2-positive tumors (n =79, 17.4%) were similar to HR-negative/HER2-negative tumors (OR 0.72, 95% CI 0.35-1.48, p =0.37); and HR-negative/HER2-positive tumors (n =92, 20.3%) were associated with increased ypN0 (OR 4.82, 95% CI 2.41-9.63, p <0.001). As ycN stage increased, the likelihood of ypN0 decreased compared with ycN0 patients (ycN1/2: OR 0.54, 95% CI 0.32-0.89, p =0.02; ycN3: OR 0.29, 95% CI 0.13-0.67, p =0.004)., Conclusions: One-third of patients with IBC who received NAC and MRM had pathologically negative nodes. Factors associated with ypN0 included ycN0 status and HR-negative/HER2-positive subtype. Large, prospective studies are needed to investigate the feasibility of alternative nodal evaluation strategies in IBC, with consideration to these subgroups.

Background: An increasing number of breast cancer patients are undergoing expanded genetic testing and are being identified as germline mutation carriers. We sought to determine rates of contralateral risk-reducing mastectomy (CRRM) in patients with various germline mutations., Patients and Methods: All women ≥ 18 years of age with unilateral breast cancer who underwent multigene panel testing between January 1, 2014 and August 1, 2019 at our academic institution were identified. Demographic, tumor, and treatment variables were identified from the medical record. Multivariable analyses were performed to compare factors associated with performance of CRRM., Results: We identified 1613 patients, of whom 28.1% had a pathogenic variant and 40.1% had variants of uncertain significance (VUS). Overall, 420 patients (26.0%) underwent a CRRM. On multivariable analysis, factors associated with CRRM included age < 50 years (OR 3.8, 95% CI 3.0, 5.0), race (OR 0.5, 95% CI 0.3, 0.7 and OR 0.4, 95% CI 0.2, 0.7 for Black and Asian women, respectively, versus White women), and the presence of any germline mutation or VUS (OR 13.2, 95% CI 8.7, 20.2 for BRCA1/2; OR 3.9, 95% CI 2.7, 5.8 for non-BRCA germline mutation; and OR 1.8, 95% CI 1.3, 2.6 for VUS)., Conclusions: In breast cancer patients who undergo multigene panel testing, a sizeable number of women with pathogenic non-BRCA germline findings are opting for CRRM. Given that the risk of contralateral breast cancer in women with most pathogenic mutations other than BRCA1/2 remains poorly characterized, these data have implications for risk counseling and for ascertaining the true risks of contralateral breast cancer in this population.

The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.

Importance: Breast cancer risk and comorbidities increase with age. Data are lacking on the association of adjuvant chemotherapy with survival in elderly patients with multiple comorbidities and node-positive breast cancer., Objective: To examine the association of chemotherapy with survival in elderly patients with multiple comorbidities and estrogen receptor-positive, node-positive breast cancer., Design, Setting, and Participants: This retrospective cohort study included patients in the US National Cancer Database who were 70 years or older; had a Charlson/Deyo comorbidity score of 2 or 3; had estrogen receptor-positive, ERBB2 (formerly HER2 or HER2/neu)-negative breast cancer; and underwent surgery for pathologic node-positive breast cancer from January 1, 2010, to December 31, 2014. Propensity scores were used to match patients receiving adjuvant chemotherapy with those not receiving adjuvant chemotherapy based on age, comorbidity score, facility type, facility location, pathologic T and N stage, and receipt of adjuvant endocrine and radiation therapy. Data analysis was performed from December 13, 2018, to April 28, 2020., Exposures: Chemotherapy., Main Outcomes and Measures: The association of adjuvant chemotherapy with overall survival was estimated using a double robust Cox proportional hazards regression model., Results: Of a total of 2 445 870 patients in the data set, 1592 patients (mean [SD] age, 77.5 [5.5] years; 1543 [96.9%] female) met the inclusion criteria and were included in the initial nonmatched analysis. Of these patients, 350 (22.0%) received chemotherapy and 1242 (78.0%) did not. Compared with patients who did not receive chemotherapy, patients who received chemotherapy were younger (mean age, 74 vs 78 years; P < .001), had larger primary tumors (pT3/T4 tumors: 72 [20.6%] vs 182 [14.7%]; P = .005), and had higher pathologic nodal burden (75 [21.4%] vs 81 [6.5%] with stage pN3 disease and 182 [52.0%] vs 936 [75.4%] with stage pN1 disease; P < .001). More patients who received chemotherapy also received other adjuvant treatments, including endocrine therapy (309 [88.3%] vs 1025 [82.5%]; P = .01) and radiation therapy (236 [67.4%] vs 540 [43.5%]; P < .001). In the matched cohort, with a median follow-up of 43.1 months (95% CI, 39.6-46.5 months), no statistically significant difference was found in median overall survival between the chemotherapy and no chemotherapy groups (78.9 months [95% CI, 78.9 months to not reached] vs 62.7 months [95% CI, 56.2 months to not reached]; P = .13). After adjustment for potential confounding factors, receipt of chemotherapy was associated with improved survival (hazard ratio, 0.67; 95% CI, 0.48-0.93; P = .02)., Conclusions and Relevance: This cohort study found that in node-positive, estrogen receptor-positive elderly patients with breast cancer and multiple comorbidities, receipt of chemotherapy was associated with improved overall survival. Despite attempts to adjust for selection bias, these findings suggest that physicians carefully selected patients likely to derive treatment benefit from adjuvant chemotherapy based on certain unmeasured variables. A standardized, multidisciplinary approach to care may be associated with long-term treatment outcomes in this subset of the population.

Background: We translated a multigene expression index to predict sensitivity to endocrine therapy for Stage II-III breast cancer (SET2,3) to hybridization-based expression assays of formalin-fixed paraffin-embedded (FFPE) tissue sections. Here we report the technical validity with FFPE samples, including preanalytical and analytical performance., Methods: We calibrated SET2,3 from microarrays (Affymetrix U133A) of frozen samples to hybridization-based assays of FFPE tissue, using bead-based QuantiGene Plex (QGP) and slide-based NanoString (NS). The following preanalytical and analytical conditions were tested in controlled studies: replicates within and between frozen and fixed samples, age of paraffin blocks, homogenization of fixed sections versus extracted RNA, core biopsy versus surgically resected tumor, technical replicates, precision over 20 weeks, limiting dilution, linear range, and analytical sensitivity. Lin's concordance correlation coefficient (CCC) was used to measure concordance between measurements., Results: SET2,3 index was calibrated to use with QGP (CCC 0.94) and NS (CCC 0.93) technical platforms, and was validated in two cohorts of older fixed samples using QGP (CCC 0.72, 0.85) and NS (CCC 0.78, 0.78). QGP assay was concordant using direct homogenization of fixed sections versus purified RNA (CCC 0.97) and between core and surgical sample types (CCC 0.90), with 100% accuracy in technical replicates, 1-9% coefficient of variation over 20 weekly tests, linear range 3.0-11.5 (log2 counts), and analytical sensitivity ≥2.0 (log2 counts)., Conclusions: Measurement of the novel SET2,3 assay was technically valid from fixed tumor sections of biopsy or resection samples using simple, inexpensive, hybridization methods, without the need for RNA purification., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes., Methods: The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process., Results: Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria., Recommendations: Patients with newly diagnosed BC and BRCA1 / 2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1 / 2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1 / 2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1 / 2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.

Rates of contralateral prophylactic mastectomy (CPM) have risen substantially, yet little is known about how and to what extent CPM is discussed within surgical oncology visits at the time of treatment decision-making. We examined CPM discussions in naturally occurring interactions between sporadic breast cancer patients and their surgical oncology providers. Women with early-stage unilateral disease were recruited before their first surgical visit and completed brief questionnaires to determine study eligibility and interest in treatment options. After their visits, enrolled patients and their providers completed questionnaires assessing discussion of and interest in CPM. Audio-recorded visits from 36 unique patients were randomly selected, transcribed, and analyzed. A CPM discussion was present in 28 transcripts. Approximately half of CPM discussions were initiated by the patient or the oncology provider. The topic of CPM was most frequently introduced while reviewing available treatment options. Patients were most interested in pursuing CPM to reduce the risk of future breast cancer. Providers most frequently responded by offering information (e.g., about risk of contralateral disease). A high level of agreement was found among patient, provider, and observer ratings of whether or not CPM was discussed. CPM discussions were consistently present within our sample. Results can be used to build providers' skills and bring provider-patient communication more in line with best practices and recommendations from leading professional medical societies., (© Society of Behavioral Medicine 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Primary endocrine therapy for ductal carcinoma in situ (DCIS) as a potential alternative to surgery has been understudied. This trial explored the feasibility of a short-term course of letrozole and sought to determine whether treatment results in measurable radiographic and biologic changes in estrogen receptor (ER)-positive DCIS., Patients and Methods: A phase II single-arm multicenter cooperative-group trial was conducted in postmenopausal patients diagnosed with ER-positive DCIS without invasion. Patients were treated with letrozole 2.5 mg per day for 6 months before surgery. Breast magnetic resonance imaging (MRI) was obtained at baseline, 3 months, and 6 months. The primary end point was change in 6-month MRI enhancement volume compared with baseline., Results: Overall, 79 patients were enrolled and 70 completed 6 months of letrozole. Of these, 67 patients had MRI data available for each timepoint. Baseline MRI volumes ranged from 0.004 to 26.3 cm 3 . Median reductions from baseline MRI volume (1.4 cm 3 ) were 0.6 cm 3 (61.0%) at 3 months ( P < .001) and 0.8 cm 3 (71.7%) at 6 months ( P < .001). Consistent reductions were seen in median baseline ER H-score (228; median reduction, 15.0; P = .005), progesterone receptor H-score (15; median reduction, 85.0; P < .001), and Ki67 score (12%; median reduction, 6.3%; P = .007). Of the 59 patients who underwent surgery per study protocol, persistent DCIS remained in 50 patients (85%), invasive cancer was detected in six patients (10%), and no residual DCIS or invasive cancer was seen in nine patients (15%)., Conclusions: In a cohort of postmenopausal women with ER-positive DCIS, preoperative letrozole resulted in significant imaging and biomarker changes. These findings support future trials of extended endocrine therapy as primary nonoperative treatment of some DCIS.

To characterize molecular changes accompanying the stepwise progression to breast cancer and to identify functional target pathways, we performed miRNA and RNA sequencing using MCF10A cell lines based model system that replicates the multi-step progression involving normal, preneoplastic, ductal carcinoma in situ, and invasive carcinoma cells, where the carcinoma most resemble the basal-like subgroup of human breast cancers. These analyses suggest that 70% of miRNA alterations occurred during the initial progression from normal to a preneoplastic stage. Most of these early changes reflected a global upregulation of miRNAs. This was consistent with a global increase in the miRNA-processing enzyme DICER, which was upregulated as a direct result of loss of miRNA let-7b-5p. Several oncogenic and tumor suppressor pathways were also found to change early, prior to histologic stigmata of cancer. Our finding that most genomic changes in the progression to basal-like breast cancer occurred in the earliest stages of histologic progression has implications for breast cancer prevention and selection of appropriate control tissues in molecular studies. Furthermore, in support of a functional significance of let-7b-5p loss, we found its low levels to predict poor disease-free survival and overall survival in breast cancer patients.

Background: Responsible opioid prescribing for postoperative pain control is critical. We sought to identify both patient and surgical factors associated with increased opioid use after breast-conserving surgery (BCS)., Methods: Patients (N = 316) undergoing BCS were surveyed to determine postoperative opioid use. Univariate and multivariate analyses were used to determine factors contributing to increased opioid use (highest quartile of use). All opioid prescriptions were converted to oral morphine equivalents (OME) for analysis., Results: The mean opioid prescription was 33.2 OMEs. Fourteen patients (4.4%) did not receive a narcotic prescription at discharge. Seventy-eight patients (24.7%) did not take any opioids after discharge. Those in the highest quartile of use consumed more than 50 OMEs. Surgical factors, such as bilateral oncoplastic surgery (60.8 OMEs vs. 33.1 OMEs, p = 0.0001), axillary lymph node dissection (ALND) (61.5 vs. 30.5, p = 0.0003), and drain use (2 drains 71.1, 1 drain 40.4, no drains 26.2, p = 0.0001), were associated with higher opioid use. In a multivariate analysis, smoking, preoperative opioid use, bilateral oncoplastic surgery, high postoperative reported pain score, placement of at least one surgical drain, and receiving a discharge prescription greater than 150 OMEs were associated with the highest quartile of opioid use., Conclusions: Smoking, preoperative opioid use, bilateral oncoplastic surgery, ALND, use of surgical drains, high reported postoperative pain score, and receiving a higher OME discharge prescription are associated with higher postoperative opioid use. Given the wide variability of analgesic needs, these criteria should be used to guide the appropriate tailoring of opioid prescriptions.

Background: The American Joint Committee on Cancer (AJCC) breast cancer pathological prognostic stage, which incorporates biologic factors, was developed using data from patients undergoing upfront surgery, and its application in patients receiving neoadjuvant chemotherapy (NAC) is unknown. We previously developed the Neo-Bioscore, incorporating clinical and pathological TNM categories with biologic factors, to improve the prognostic stratification of NAC patients., Objective: This study was undertaken to evaluate the use of available staging models incorporating biologic factors in NAC patients., Methods: Patients treated with NAC between 2005 and 2012 at MD Anderson (n = 2363) were staged using the Neo-Bioscore and the AJCC 8th edition: (1) clinical anatomic stage; (2) pathological anatomic stage; (3) clinical prognostic stage; and (4) pathological prognostic stage. Five-year disease-specific survival (DSS) and overall survival (OS) rates, along with Harrell's concordance index (C-index), were estimated. A National Cancer Database (NCDB) cohort (n = 12,887) treated with NAC between 2010 and 2013 was used for validation., Results: In the MD Anderson cohort, staging systems incorporating biologic factors better predicted DSS (bias-corrected C-index: pathological prognostic stage = 0.8026; Neo-Bioscore = 0.7483) and OS (bias-corrected C-index: pathological prognostic stage = 0.7780; Neo-Bioscore = 0.7260) than those using anatomic factors only. Similar results were seen in the NCDB cohort. In pairwise comparisons, the pathological prognostic stage was significantly better (p < 0.0001) than other staging systems in all comparisons except for OS in the NCDB cohort, where it was not significantly different than the Neo-Bioscore (p = 0.2)., Conclusion: Biologic factors are important for determining prognosis in patients receiving NAC. These data indicate that the 8th edition AJCC pathological prognostic stage is applicable in these patients.

Purpose : Metaplastic breast cancer (BC) is an uncommon yet aggressive histologic subtype of BC. We sought to identify factors associated with its diagnosis and compare the management and outcomes of metaplastic BC with those of other BCs and triple negative invasive ductal carcinoma in particular given how often it has a triple negative phenotype. Patients and Methods : We identified women diagnosed with invasive BC in 2010-2014 in the National Cancer Data Base, and used univariate analysis to compare baseline patient and tumor characteristics by BC subtype. Overall survival (OS) was estimated with the Kaplan-Meier method, and multivariate Cox proportional hazards models were used to identify independent predictors of OS. Results : Of 247,355 cases, 2,084 (0.8%) were metaplastic BC, 55,998 (23%) triple negative BC, and 77% other BC. Relative to non-metaplastic BC, women with metaplastic BC were more likely to be older at diagnosis (median age, 62 vs. 59 years), have ≥1 comorbid conditions (22% vs. 18%), and be on Medicare (41% vs. 33%; P <0.001). Metaplastic BCs tended to be basal-like (77%), and relative to triple-negative or other BC, metaplastic BC was associated with higher clinical T status (cT3-4, 18% vs. 11%, 8%), no clinical nodal involvement (cN0, 86%, 77%, 80%), no lymphovascular invasion (72%, 65%, 62%), and high-grade tumors (71%, 77%, 35%) ( P <0.001). Most metaplastic BCs were treated with mastectomy (58%), sentinel lymph node dissection (65%), chest wall or breast irradiation (74%), and chemotherapy (75%) as adjuvant therapy (60%). At a median follow-up time of 44.5 months, OS rates were lower for metaplastic BC than for triple-negative or other BC across all clinical stages at 5 years (stage I, 85%, 87%, 91%; II, 73%, 77%, 87%; III, 43%, 53%, 75%) and at 3 years (Stage IV, 15%, 22%, 64%; P <0 . 001). On multivariate analysis, increasing age, advanced clinical stage, lymphovascular invasion, axillary (vs. sentinel) node dissection, and no radiation or chemotherapy were associated with worse outcomes in metaplastic BC. Extent of surgery affected survival for triple-negative and other BC but not for metaplastic BC. Conclusion : Outcomes for metaplastic BC continue to be worse than those for other BC subtypes despite modern treatments. Optimizing systemic therapy options, which was a significant predictor of survival, should be a priority in managing metaplastic BC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Family history is an important cancer risk assessment tool, and it is easy to use. The family history is integral in identifying an individual's risk for primary cancer and assists in the assessment of risk for a second primary cancer. For oncology providers, the critical family history is defined as including first- and second-degree family history, maternal and paternal history, type of primary cancer, and age at diagnosis and ethnicity. Family history should be taken at diagnosis and updated periodically. Despite the importance of family history to patient care, there are significant barriers to taking a family history. We review the impact of collecting complete family history data with respect to calculation of cancer risk, recommendations for screening, and prevention strategies and referral for genetic testing., (© 2019 Wiley Periodicals, Inc.)

Background: American College of Surgeons Oncology Group Z0011 confirms the safety of omitting axillary lymph node dissection (ALND) and regional nodal irradiation (RNI) in breast cancer patients with one to two positive sentinel lymph nodes (SLNs), without compromising disease-free survival (DFS) and overall survival (OS). In contrast, the NCIC MA20 trial showed improved DFS in node-positive patients undergoing ALND and RNI. We sought to examine how these data have influenced the management of patients with limited nodal burden., Methods: Using the National Cancer Database, patients diagnosed between 2010 and 2015 and who met the criteria for Z0011 were identified. Logistic regression was used to analyze factors associated with practice patterns. The Cox proportional hazards model was used to assess the association of ALND and RNI with OS., Results: Omission of ALND in Z0011-eligible patients reached 89.2% in 2015. This Z0011-compliant group was more likely to undergo RNI compared with the non-compliant group (36.4% vs. 31.3%; p < 0.05), with RNI increasing to 43.8% by 2015. Factors associated with the use of RNI included later year of diagnosis [odds ratio (OR) 1.8, 95% confidence interval (CI) 1.6-2.1], hormone receptor-negative tumor (OR 1.2, 95% CI 1.1-1.4), grade 3 tumor (OR 1.2, 95% CI 1.1-1.3), treatment at a non-academic site (OR 1.2, 95% CI 1.1-1.3) and two versus one positive SLN (OR 2.0, 95% CI 1.8-2.2). With 43 months median follow-up, RNI was not associated with improved OS., Conclusion: Since the publication of Z0011, the omission of ALND has become widespread; however nearly half of these women now receive RNI. The optimal radiation therapy approach for this low nodal burden population warrants further study.

Purpose: Deintensification of adjuvant therapy is being considered for older women with early-stage, biologically favorable breast cancer. Although radiation therapy (RT) can be omitted in some cases, toxicity from hormone therapy (HT) is not trivial, and adherence rates vary. We hypothesized that adjuvant RT alone would produce survival outcomes comparable to those with adjuvant HT alone among elderly patients treated with lumpectomy., Methods and Materials: We searched the National Cancer Database (2010-2014) for healthy women (aged ≥70 years, Charlson/Deyo [CD] score 0-1) with T1N0 hormone-receptor-positive, HER-2-negative breast cancer treated with lumpectomy and adjuvant HT or RT. Propensity scores were used to match patients for analysis., Results: We identified 2995 patients (median age, 78 years), most (81%) with a CD score of 0, clinical stage IA (77%), of whom 65% received HT alone and 35% received RT only after lumpectomy. On multivariate analysis of the matched cohort, older age (hazard ratio [HR] 1.10; 95% confidence interval [CI] 1.07-1.13; P < .001), CD score 1 (HR 1.92; 95% CI 1.37-2.70; P = .0002), and living in a metropolitan (vs urban) area (HR 3.09; 95% CI 1.43-6.67; P = .004) were associated with inferior overall survival (OS), whereas treatment with HT (vs RT) was not (HR 1.13; 95% CI 0.85-1.49; P = .406). At a median follow-up of 45 months, no difference was found in OS between HT versus RT cohorts (85% and 86%, respectively; P = .44)., Conclusions: For healthy, older women with biologically favorable breast cancer treated with lumpectomy, adjuvant RT or HT is associated with equivalent 5-year OS rates. A randomized controlled trial is warranted to explore these adjuvant monotherapy options in elderly patients with hormone receptor-positive breast cancer., (Published by Elsevier Inc.)

Background: Prospective lymphedema screening is recommended for breast cancer patients. We observed interoperator variation in perometer-acquired arm volume measurements (P-AVMs) due to patient instability during measurements. We hypothesized that improved positioning during perometry would reduce P-AVM variability. Methods and Results: Each arm was measured three times by each operator using a perometer. With the original configuration, P-AVM was performed by 2 operators in 30 patients and four cohorts of 5 to 6 operators in 5 volunteers. Repeatability, reproducibility, and gage precision/tolerance (P/T) ratio were calculated. A customized handlebar was installed to optimize patient positioning. P-AVMs were performed in 20 patients with both configurations. Student's t -test was used to compare variation. With the new configuration, P-AVMs were performed by three operators in five volunteers and five operators in three volunteers. Repeatability, reproducibility, and gage P/T ratio were calculated. For the original configuration, gage P/T ratio was 19.9% for two operators and 35.9% for four cohorts of five to six operators. One operator using the new handlebar decreased P-AVM variability by 28% ( p  = 0.02). For the new configuration, gage P/T ratio was 6.5% for three operators and 18.7% for five operators. Conclusions: Optimizing patient setup improved P-AVM accuracy. P-AVM accuracy is critical as lack of accuracy results in either overdiagnosis or underdiagnosis of lymphedema, which in turn results in either over- or undertreatment of this dreaded condition. A higher number of operators were associated with greater P-AVM variability.

Purpose: The optimal management of breast cancer patients with a positive sentinel lymph node (SLN) who undergo mastectomy remains controversial. This study aimed to describe treatment patterns of patients with positive SLNs who undergo mastectomy using a large population-based database., Methods: The NCDB was queried for cT1-2N0 breast cancer patients treated with mastectomy between 2006 and 2014 who had 1-2 positive SLNs. Patients receiving neoadjuvant chemotherapy were excluded. Axillary management included SLN dissection (SLND) alone, axillary lymph node dissection (ALND), post-mastectomy radiation (PMRT) alone, and ALND + PMRT. Trends of axillary management and patient characteristics were examined., Results: Among 12,190 patients who met study criteria, the use of ALND dropped with a corresponding increase in other approaches. In 2006, 34% of patients had SLND alone, 47% ALND, 8% PMRT and 11% ALND + PMRT. By 2014, 37% had SLND, 23% ALND, 27% PMRT and 13% ALND + PMRT. Patients who underwent SLND alone were older (mean 60.6 years) with more comorbidities (Charlson-Deyo score > 2), smaller primary tumors (mean 2.1 cm), well-differentiated histology, hormone receptor-positive, HER2-negative tumors, without lymphovascular invasion (all P values < 0.01). Treatment with SLND alone was more likely if patients had only one positive SLN (P < 0.001) or micrometastatic disease (P < 0.001), and were treated at community centers compared with academic centers (P < 0.001)., Conclusions: The management of breast cancer patients undergoing mastectomy with positive SLNs has evolved over time with decreased use of ALND and increased use of radiation. Some patient subsets are underrepresented in recent clinical trials, and therefore, future trials should focus on these patients.

Background: Few guidelines exist for an opioid prescription after breast surgical oncology (BSO) procedures. We sought to characterize opioid prescribing and use patterns by surgery type., Methods: Patients (n = 332) undergoing BSO procedure were surveyed one week postoperatively for opioid use. The surgeons were surveyed about pain management preferences surgery type. CPT codes were collected for 2017 to calculate the amount of opioids used by surgery type relative to surgeon preference., Results: Mean oral morphine equivalent (OME) preferred prescription for surgeons who did not tailor prescriptions by surgery type (n = 7, group A) was 177, whereas for those who did tailor (n = 10, group B) varied from 137 to 257 OME. There was a significant difference in opioid use by surgery type: 32 OME for segmental mastectomy (SM) ± sentinel lymph node dissection (SLND), 63 for SM + axillary lymph node dissection (ALND), 76 for total mastectomy (TM) ± SLND, 115 for TM + ALND (P < 0.001). Considering the type of surgeries performed group A prescribers would have 229190 unused OME and group B would have 230826 in 1 year., Conclusion: Wide variation in opioid use by BSO procedure type was noted with substantial unused OME regardless ofprescribing preference. Evidence-based guidelines are needed to tailor analgesic prescriptions according to the need., (© 2019 Wiley Periodicals, Inc.)

Greater use of neoadjuvant chemotherapy in patients with breast cancer has led surgeons and radiation oncologists to have frequent encounters with women with upfront node-positive disease and a clinical complete response. These cases raise many important questions about what the optimal locoregional management should be to minimize recurrence risk while minimizing treatment-related toxicities. A particular point of debate is whether all patients who are known to have had node-positive disease before neoadjuvant chemotherapy should receive complete axillary lymph node dissection (ALND) if they have had a complete clinical and radiologic response. In this article, we present arguments and evidence in favor of and against axillary dissection after a complete response to neoadjuvant chemotherapy, followed by a brief data-driven review of implications for adjuvant radiotherapy in this context. We conclude that as trials continue to gather more evidence to guide decisions in the future, we must encourage patients to enroll in clinical trials when eligible, and otherwise support them to make decisions that are informed and congruent with their personal values in areas where there is clinical equipoise.

Purpose: This study aimed to prospectively characterize toxicity and cosmesis after accelerated partial breast irradiation (APBI) with 3-dimensional conformal radiation therapy (CRT) or single-entry, multilumen, intracavitary brachytherapy., Methods and Materials: A total of 281 patients with pTis, pT1N0, or pT2N0 (≤3.0 cm) breast cancer treated with segmental mastectomy were prospectively enrolled from December 2008 through August 2014. APBI was delivered using 3-dimensional CRT (n = 29) or with SAVI (n = 176), Contura (n = 56), or MammoSite (n = 20) brachytherapy catheters. Patients were evaluated at protocol-specified intervals, at which time the radiation oncologist scored cosmetic outcome, toxicities, and recurrence status using a standardized template., Results: The median follow-up time is 41 months. Grade 1 seroma and fibrosis were more common with brachytherapy than with 3-dimensional CRT (50.4% vs 3.4% for seroma; P < .0001 and 66.3% vs 44.8% for fibrosis; P = .02), but grade 1 edema was more common with 3-dimensional CRT than with brachytherapy (17.2% vs 5.6%; P = .04). Grade 2 to 3 pain was more common with 3-dimensional CRT (17.2% vs 5.2%; P = .03). Actuarial 5-year rates of fair or poor radiation oncologist-reported cosmetic outcome were 9% for 3-dimensional CRT and 24% for brachytherapy (P = .13). Brachytherapy was significantly associated with inferior cosmesis on mixed model analysis (P = .003). Significant predictors of reduced risk of adverse cosmetic outcome after brachytherapy were D0.1cc (skin) ≤102%, minimum skin distance >5.1 mm, dose homogeneity index >0.54, and volume of nonconformance ≤0.89 cc. The 5-year ipsilateral breast recurrence was 4.3% for brachytherapy and 4.2% for 3-dimensional CRT APBI patients (P = .95)., Conclusions: Brachytherapy APBI is associated with higher rates of grade 1 fibrosis and seroma than 3-dimensional CRT but lower rates of grade 1 edema and grade 2 to 3 pain than 3-dimensional CRT. Rates of radiation oncologist-reported fair or poor cosmetic outcomes are higher with brachytherapy. We identified dosimetric parameters that predict reduced risk of adverse cosmetic outcome after brachytherapy-based APBI. Ipsilateral breast recurrence was equivalent for brachytherapy and 3-dimensional CRT., (Copyright © 2018 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: Prevention of triple-negative breast cancer (TNBC) is hampered by lack of knowledge about the drivers of tumorigenesis., Methods: To identify molecular markers and their downstream networks that can potentially be targeted for TNBC prevention, we analyzed small RNA and RNA sequencing of a cell line model that represent early stages of TNBC development. We have identified direct gene targets of isomiRNA-140-3p and by using cell-based and in vivo model systems we have demonstrated the utility of targeting downstream pathways for prevention of TNBC., Results: These analyses showed that 5'isomiRNA of miR-140-3p (miR-140-3p-1) and its novel direct gene targets, HMG-CoA reductase (HMGCR) and HMG-CoA synthase 1(HMGCS1), key enzymes in the cholesterol biosynthesis pathway, were deregulated in the normal-to-preneoplastic transition. Upregulation in the cholesterol pathway creates metabolic vulnerability that can be targeted. Consistent with this hypothesis, we found direct targeting of miR-140-3p-1 and its downstream pathway by fluvastatin to inhibit growth of these preneoplastic MCF10.AT1 cells. However, although, fluvastatin inhibited the growth of MCF10.AT1-derived xenografts, histological progression remained unchanged. The cholesterol pathway is highly regulated, and HMGCR enzymatic activity inhibition is known to trigger a feedback response leading to restoration of the pathway. Indeed, we found fluvastatin-induced HMGCR transcript levels to be directly correlated with the degree of histological progression of lesions, indicating that the extent of cholesterol pathway suppression directly correlates with abrogation of the tumorigenic process. To block the HMGCR feedback response to statins, we treated resistant preneoplastic cells with an activator of AMP-activated protein kinase (AMPK), a brake in the cholesterol feedback pathway. AMPK activation by aspirin and metformin effectively abrogated the statin-induced aberrant upregulation of HMGCR and sensitized these resistant cells to fluvastatin., Conclusions: These results suggest the potential use of combined treatment with statin and aspirin for prevention of TNBC.

Purpose The incidence of contralateral prophylactic mastectomy (CPM) has continued to increase. We prospectively examined psychosocial outcomes before and up to 18 months after surgery in women who did or did not have CPM. Methods Women with unilateral, nonhereditary breast cancer completed questionnaires before and 1, 6, 12, and 18 months after surgery. Primary psychosocial measures were cancer worry and cancer-specific distress. Secondary measures were body image, quality of life (QOL), decisional satisfaction, and decisional regret. Results A total of 288 women (mean age, 56 years; 58% non-Hispanic white) provided questionnaire data, of whom 50 underwent CPM. Before surgery, women who subsequently received CPM had higher cancer distress ( P = .04), cancer worry ( P < .001), and body image concerns ( P < .001) than women who did not have CPM. In a multivariable repeated measures model adjusted for time, age, race/ethnicity, and stage, CPM was associated with more body image distress ( P < .001) and poorer QOL ( P = .02). There was a significant interaction between time point and CPM group for cancer worry ( P interaction < .001), suggesting that CPM patients had higher presurgery cancer worry, but their postsurgery worry decreased over time and was similar to the worry of patients who did not have CPM. QOL was similar between CPM groups before surgery but declined 1 month after surgery and remained lower than patients who did not have CPM after surgery ( P interaction = .05). Conclusion These results may facilitate informed discussions between women and their physicians regarding CPM. Fear and worry may be foremost concerns at the time surgical decisions are made, when women may not anticipate the adverse future effect of CPM on body image and QOL.