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Background Nipple-sparing mastectomy is associated with a higher risk of mastectomy skin-flap necrosis than conventional skin-sparing mastectomy. There are limited prospective data examining modifiable intraoperative factors that contribute to skin-flap necrosis after nipple-sparing mastectomy. Methods Data on consecutive patients undergoing nipple-sparing mastectomy between April 2018 and December 2020 were recorded prospectively. Relevant intraoperative variables were documented by both breast and plastic surgeons at the time of surgery. The presence and extent of nipple and/or skin-flap necrosis was documented at the first postoperative visit. Necrosis treatment and outcome was documented at 8–10 weeks after surgery. The association of clinical and intraoperative variables with nipple and skin-flap necrosis was analysed, and significant variables were included in a multivariable logistic regression analysis with backward selection. Results Some 299 patients underwent 515 nipple-sparing mastectomies (54.8 per cent (282 of 515) prophylactic, 45.2 per cent therapeutic). Overall, 23.3 per cent of breasts (120 of 515) developed nipple or skin-flap necrosis; 45.8 per cent of these (55 of 120) had nipple necrosis only. Among 120 breasts with necrosis, 22.5 per cent had superficial, 60.8 per cent had partial, and 16.7 per cent had full-thickness necrosis. On multivariable logistic regression analysis, significant modifiable intraoperative predictors of necrosis included sacrificing the second intercostal perforator (P = 0.006), greater tissue expander fill volume (P < 0.001), and non-lateral inframammary fold incision placement (P = 0.003). Conclusion Modifiable intraoperative factors that may decrease the likelihood of necrosis after nipple-sparing mastectomy include incision placement in the lateral inframammary fold, preserving the second intercostal perforating vessel, and minimizing tissue expander fill volume.

PurposeThe Breast Cancer Surveillance Consortium (BCSC) model predicts risk of invasive breast cancer risk based on age, race, family history, breast density, and history of benign breast disease, including lobular carcinoma in situ (LCIS). However, validation studies for this model included few women with LCIS. We sought to evaluate the accuracy of the BCSC model among this cohort. MethodsWomen with LCIS diagnosed between 1983 and 2017 were identified from a prospectively maintained database. The BCSC score was calculated; those with prior breast cancer, unknown breast density, aged 74 or history of chemoprevention use were excluded. The Kaplan-Meier method was used to estimate incidence rates. Time-dependent receiver operating characteristic (ROC) analysis was used to analyze the discriminative capacity of the model. Results1302 women with LCIS were included. At a median follow-up of 7 years, 152 women (12%) developed invasive cancer (6 with bilateral disease). Cumulative incidences of invasive breast cancer were 7.1% (95% CI 5.6, 8.7) and 13.3% (95% CI 10.9,15.6), respectively, and the median BCSC risk scores were 4.9 and 10.4, respectively, at 5 and 10 years. The median 10year BCSC score was significantly lower than the 10-year Tyrer-Cuzick score (10.4 vs 20.8, p

Axillary lymph node status in patients with breast cancer is an important prognostic indicator and often guides vital treatment decisions. Although in many cases imaging plays a crucial role in the assessment of the axilla, it is essential that targeted axillary US and/or image-guided biopsy of an axillary lymph node be performed by the radiologist only when clinically appropriate. This decision-making process requires multidisciplinary communication and collaboration among radiologists, surgeons, medical oncologists, and radiation oncologists. Our goal is to review axillary imaging for patients with breast cancer in two distinct clinical settings, the patient with newly diagnosed breast cancer who meets American College of Surgeons Oncology Group Z0011 criteria and patients undergoing neoadjuvant chemotherapy, with a specific focus on potential reasons to not perform axillary US and/or image-guided biopsy in these settings.

National guidelines recommend against routine axillary staging with sentinel lymph node biopsy (SLNB) and adjuvant radiotherapy (RT) in women ≥70 y with early-stage, hormone receptor-positive, HER2-negative breast cancer and clinically negative axilla; however, these practices remain common.We conducted a prospective pilot study from August 2021 to 2022 using an intervention targeting breast surgeons and radiation oncologists in Michigan that aimed to reduce SLNB and RT in eligible patients. The intervention consisted of (1) a geriatric assessment, (2) an assessment of the patient's medical maximizing-minimizing preferences, and (3) a tailored script with counterpoints to reasons patients commonly seek SLNB or RT. At the end of the study period, participants completed a survey providing feedback with the primary outcomes being: acceptability, appropriateness, feasibility, and intention and motivation to use the materials based on validated measures.Participants (n = 23) included 15 breast surgeons and 8 radiation oncologists. Collectively, the materials were used with 115 patients. Considering all materials holistically, acceptability, appropriateness, and feasibility of the intervention were high; participants also intended and were motivated to use the intervention. Scores across all measures were highest for the geriatric assessment and lowest for the tailored script. The major barriers to using the intervention were limited time and instances of disagreement on treatment recommendations among surgeons and radiation oncologists.The omission of SLNB and adjuvant RT should be discussed in appropriately selected patients. A multifaceted provider-level deimplementation strategy may be an effective means for achieving this goal.

Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes. A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores. Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26 kg/m2, p

Background: Adjuvant oral tamoxifen (TAM) benefits women with DCIS, but toxicity concerns have limited its acceptance. Transdermal therapy with 4-hydroxy tamoxifen (4-OHT) gel applied to the breast skin is a possible solution. Previous pilot data suggest equivalent anti-proliferative efficacy of TAM and 4-OHT gel, but minimal systemic exposure with transdermal therapy. We report a prospective double blinded randomized phase 2 trial comparing TAM to 4-OHT gel in women with DCIS. Methods: 107 women with estrogen receptor positive (≥10%) DCIS were randomized to TAM (20 mg/day + placebo gel) or 4-OHT gel (2mg 4-OHT gel/breast, bilaterally + oral placebo), for 4-10 weeks prior to surgery. The primary endpoint was reduction in DCIS Ki67 labeling index (LI). Secondary endpoints included the 12-gene DCIS Score assay (Exact Sciences), breast tissue and plasma concentrations of 4-OHT and endoxifen, TAM-responsive circulating proteins, and patient reported symptoms (Breast Eight Symptom Scale). We estimated that 80 evaluable participants would provide 80.5% power to establish non-inferiority of 4-OHT, defined as relative Ki67-LI decline >35% and absolute decline >2.6%, with one-sided 𝛼=0.10. Non-inferiority of 4-OHT gel for Ki67-LI reduction was tested using an ANCOVA model. Statistical comparisons within- and between-arms were calculated with paired t-test and Welch Two Sample t-test, respectively. Results: 72 of 87 women adhered to the protocol, and were evaluable for the primary endpoint (39 TAM and 33 4-OHT gel). Mean treatment duration was 47 days for TAM and 44 days for 4-OHT gel (p=0.2). The median absolute decline in Ki67 labeling index was significant in the oral TAM (-3.7%, p< 0.001) but not in 4-OHT gel arm (-1.3%, p=0.2) (p=0.002). Ki67 results following menopausal stratification also favored the TAM arm: (-1.3%; p=0.06 in 37 premenopausal women and -3.7%; p=0.02 in 35 postmenopausal women). Similarly, DCIS score showed a significantly greater reduction in the TAM (-14, p< 0.001) but not in the 4-OHT gel arm (-4, p=0.1). Tissue 4-OHT concentrations were non-significantly higher in the TAM arm and were similar between superficial and deep sampling locations (superficial 6.1 and 4.2 ng/g for TAM and 4-OHT gel, respectively, p= 0.55; deep 5.7 and 3.8 ng/g, respectively, p= 0.06), whereas plasma 4-OHT concentration was markedly lower in the gel group (2 ng/mL and 0.24 ng/mL for TAM and 4-OHT gel, respectively, P < 0.001). Endoxifen was abundant in plasma (11 ng/mL) and deep tissue (13 ng/g) of the TAM arm, but present in trace amounts in the 4-OHT gel arm (undetectable in plasma and 0.31 ng/g in tissue; p < 0.001). Circulating TAM responsive markers (insulin like growth factor 1, sex hormone binding globulin, von Willebrand factor, and protein S total) and vasomotor symptoms were significantly and unfavorably modulated by TAM, but not by 4-OHT gel therapy. Conclusions: The non-inferiority of transdermal 4-OHT gel to Tam in terms of anti-proliferative effect in DCIS lesions was not demonstrated at the doses used for this study. DCIS Score analysis gave similar results. Tissue 4-OHT concentration in 4-OHT gel and Tam-treated subjects was roughly similar. However, endoxifen exposure was higher with oral TAM therapy and may partially explain the observed differences in major endpoints. In future studies, use of higher 4-OHT gel doses, longer duration of treatment, or different formulation may overcome these. Citation Format: Oukseub Lee, Xinlei Mi, Yanfei Xu, Luis Blanco, Azza M. Akasha, Kelly Benante, Shanshan Zhang, Carissa LaBoy, Thomas Helland, Melissa Pilewskie, Amy Degnim, Zahraa Al-Hilli, Amanda L. Amin, E Shelley Hwang, Joseph M. Guenther, Simon Steinar Hustad, Demirkan B. Gursel, Masha Kocherginsky, Gunnar Mellgren, Eileen Dimond, Marjorie Perloff, Brandy M. Heckman-Stoddard, Seema Khan. PD15-12 A pre-surgical window trial of oral tamoxifen versus transdermal 4-hydroxytamoxifen gel in women with estrogen receptor positive duct carcinoma in situ (DCIS) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-12.

Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high-risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double-blind, placebo-controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3-336) in the oral vs. 2.82 (IQR: 1.4-5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R2 = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P

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. 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. 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. 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.

Neoadjuvant chemotherapy (NAC) is increasingly used for clinically node-positive (cN+) tumors with intact primary breast cancer (IPBC) to downstage the axilla, and those who convert to cN0 may be eligible for sentinel lymph node biopsy (SLNB). Rates of axillary downstaging in occult primary breast cancer (OPBC) are unknown. The aim of this study was to determine the frequency of nodal pathologic complete response (pCR) following NAC in a cohort of patients with OPBC. Twenty-eight patients with stage II/III OPBC treated between January 2008 and December 2019 were identified. Twenty patients had cN1-3 OPBC, pretreatment lymph node needle biopsy, and received NAC; these constituted the study population. Treatment factors and nodal pCR rates were summarized by tumor subtype. Median age at diagnosis was 54 years. Most patients presented with cN1 disease (75%) and ductal histology (80%). Nodal pCR was seen in 16/20 (80%) patients. Eight (40%) patients were triple negative, 6 (30%) were estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER +/HER2 −), and 6 (30%) were HER2 positive, with pCR rates of 88%, 50%, and 100%, respectively. Among the 15 patients who presented as cN1, 14 (93%) converted to cN0 following NAC. Of these, nine underwent SLNB and all achieved nodal pCR (100%). In this small series, 80% of OPBC patients achieved nodal pCR following NAC. pCR rates varied by receptor profile, being lowest in the ER positive/HER2 negative group and highest in the HER2 positive group (50–100%); however, these rates are excellent and numerically exceed those in the literature for IPBC. Given the pCR rate, SLNB may be an option in select OPBC patients who downstage following NAC.

In the ACOSOG (American College of Surgeons Oncology Group) Z0011 trial and the AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery?) trial, matted nodes with gross extracapsular extension (ECE), a risk factor for locoregional recurrence, were an indication for axillary lymph node dissection (ALND), but the effect of microscopic ECE (mECE) in the sentinel lymph nodes (SLNs) on recurrence was not examined. Between 2010 and 2017, 811 patients with cT1-2N0 breast cancer and SLN metastasis were prospectively managed according to Z0011 criteria, with ALND for those with more than two positive SLNs or gross ECE. Management of mECE was not specified. In this study, we compare outcomes of patients with one to two positive SLNs with and without mECE, treated with SLN biopsy alone (n = 685). Median patient age was 58 years, and median tumor size was 1.7 cm. mECE was identified in 210 (31%) patients. Patients with mECE were older, had larger tumors, and were more likely to be hormone receptor positive and HER2 negative, have two positive SLNs, and receive nodal radiation. At a median follow-up of 41 months, no isolated axillary failures were observed. There were 11 nodal recurrences; two supraclavicular ± axillary, four synchronous with breast, and five with distant failure. The five-year rate of any nodal recurrence was 1.6% and did not differ by mECE (2.3% vs. 1.3%; p = 0.84). No differences were observed in local (p = 0.08) or distant (p = 0.31) recurrence rates by mECE status. In Z0011-eligible patients, nodal recurrence rates in patients with mECE are low after treatment with SLN biopsy alone, even in the absence of routine nodal radiation. The presence of mECE should not be considered a routine indication for ALND.

Importance Prospective trials have demonstrated sentinel lymph node (SLN) false-negative rates of less than 10% when 3 or more SLNs are retrieved in patients with clinically node-positive breast cancer rendered clinically node-negative with neoadjuvant chemotherapy (NAC). However, rates of nodal recurrence in such patients treated with SLN biopsy (SLNB) alone are unknown because axillary lymph node dissection (ALND) was performed in all patients, limiting adoption of this approach. Objective To evaluate nodal recurrence rates in a consecutive cohort of patients with clinically node-positive (cN1) breast cancer receiving NAC, followed by a negative SLNB using a standardized technique, and no further axillary surgery. Design, Setting, and Participants From November 2013 to February 2019, a cohort of consecutively identified patients with cT1 to cT3 biopsy-proven N1 breast cancer rendered cN0 by NAC underwent SLNB with dual tracer mapping and omission of ALND if 3 or more SLNs were identified and all were pathologically negative. Metastatic nodes were not routinely clipped, and localization of clipped nodes was not performed. The study was performed in a single tertiary cancer center. Intervention Omission of ALND in patients with cN1 breast cancer after NAC if 3 or more SLNs were pathologically negative. Main Outcome and Measures The primary outcome was the rate of nodal recurrence among patients with cN1 breast cancer treated with SLNB alone after NAC. Results Of 610 patients with cN1 breast cancer treated with NAC (median [IQR] age, 49 [40-58] years), 555 (91%) converted to cN0 and underwent SLNB; 234 (42%) had 3 or more negative SLNs and had SLNB alone. Median age was 49 years. Median tumor size was 3 cm; 144 (62%) wereERBB2(formerlyHER2)-positive, and 43 (18%) were triple negative. Most (212 [91%]) received doxorubicin-based NAC, 205 (88%) received adjuvant radiotherapy (RT), and 164 (70%) also received nodal RT. At a median follow-up of 40 months, there was 1 axillary nodal recurrence synchronous with local recurrence in a patient who refused RT. Among patients who received RT (n = 205), there were no nodal recurrences. Conclusions and Relevance This cohort study found that in patients with cN1 disease rendered cN0 with NAC, with 3 or more negative SLNs with SLNB alone, nodal recurrence rates were low, without routine nodal clipping. These findings potentially support omitting ALND in such patients.

Importance In clinical practice, neoadjuvant endocrine therapy (NET) is rarely used despite being an effective treatment modality able to downstage tumors and facilitate breast-conserving surgery. Observations Using data from studies conducted since 2000, we provide readers with a critical in-depth review on clinical aspects related to the application of NET in the treatment of hormone receptor (HR)-positive/ERBB2 (formerly HER2)-negative breast cancer. This includes an overview of patient-selection criteria, regimen choice, treatment duration, evaluation of response by imaging, interpretation of pathology after treatment, and surgical considerations. Areas of controversy include the use of gene-expression tests for patient selection, treatment of premenopausal women, surgical management of the axilla after NET, and adjuvant systemic therapy decision-making, including the use of chemotherapy. Conclusions and relevance NET is an optimal treatment modality for a considerable proportion of postmenopausal women diagnosed with HR-positive tumors. The treatment landscape for HR-positive breast cancer is evolving, with novel agents and the growing use of gene expression profiling to define treatment selection. As such, it is likely that NET use will increase and the practical considerations outlined here will become more important.

Studies report low upgrade rates following excision for classic-type lobular carcinoma in situ (LCIS) with radiologic-pathologic concordance. Thus, in the absence of other high-risk lesions, observation has become standard. We report long-term outcomes of excision versus observation following a core biopsy diagnosis of classic-type LCIS. Women with LCIS treated from 2013-2020 and managed with excision or observation were identified from a prospective database. Women with cancer upgrade at excision or history of cancer were excluded. We compared rates and characteristics of subsequent breast cancers by clinical management strategy. Of 312 women, 170 (54%) underwent excision and 142 (46%) were managed with observation. Among the excision group, 36 of 170 (21%) had radiologic-pathologic concordant LCIS without other high-risk lesions, mass, or symptoms (concordant LCIS excision group). Overall, at 3.1 years median follow-up, 11 (6.5%) women managed with excision and 11 (7.7%) women managed with observation developed cancer. Cancer development was not associated with management choice (overall excision cohort vs. observation group [p = 0.8]) and did not differ between the concordant LCIS excision and observation groups (p > 0.9). The 5-year cancer development rate was 8.9% (95% confidence interval [CI]: 2.3–31.6%) in the concordant LCIS excision group and 10.3% (95% CI 5.5–18.6%) in the observation group. No difference in breast cancer rates existed among women with a core-biopsy diagnosis of classic-type LCIS managed with excision or observation. These data support management of LCIS as a risk factor, with consideration of chemoprophylaxis, rather than as an indication for surgical excision.

Background The Tyrer-Cuzick model has been shown to overestimate risk in women with atypical hyperplasia, although its accuracy among women with lobular carcinoma in situ (LCIS) is unknown. We evaluated the accuracy of the Tyrer-Cuzick model for predicting invasive breast cancer (IBC) development among women with LCIS. Methods Women with LCIS participating in surveillance from 1987 to 2017 were identified from a prospectively maintained database. Tyrer-Cuzick score (version 7) was calculated near the time of LCIS diagnosis. Patients with prior or concurrent breast cancer, a BRCA mutation, receiving chemoprevention, or with pleomorphic LCIS were excluded. Invasive cancer-free probability was estimated using the Kaplan-Meier method. Results A total of 1192 women with a median follow-up of 6 years (interquartile range [IQR] 2.5-9.9) were included. Median age at LCIS diagnosis was 49 years (IQR 45-55), 88% were white; 37% were postmenopausal, 28% had ≥ 1 first-degree family member with breast cancer, and 13% had ≥ 2 second-degree family members with breast cancer. In total, 128 patients developed an IBC; median age at diagnosis was 54 years (IQR 49-61). Five- and 10-year cumulative incidences of invasive cancer were 8% (95% confidence interval [CI] 6-9%) and 14% (95% CI 12-17%), respectively. The median Tyrer-Cuzick 10-year risk score was 20.1 (IQR 17.4-24.3). Discrimination measured by the C-index was 0.493, confirming that the Tyrer-Cuzick model is not well calibrated in this patient population. Conclusions The Tyrer-Cuzick model is not accurate and may overpredict IBC risk for women with LCIS, and therefore should not be used for breast cancer risk assessment in this high-risk population.

Lobular carcinoma in situ (LCIS) is a risk factor for breast cancer, but the effect of LCIS found in association with ductal carcinoma in situ (DCIS) is unknown. In this study, we compared contralateral breast cancer (CBC) and ipsilateral breast tumor recurrence (IBTR) rates among women with DCIS with or without synchronous ipsilateral LCIS treated with breast-conserving surgery (BCS). DCIS patients undergoing BCS from 2000 to 2011 with a contralateral breast at risk were stratified by the presence or absence of synchronous ipsilateral LCIS with the index DCIS (DCIS + LCIS vs. DCIS). Those with contralateral, bilateral, or prior ipsilateral LCIS were excluded. Associations of patient, tumor, and treatment factors with CBC and IBTR were evaluated. Of 1888 patients identified, 1475 (78%) had DCIS and 413 (22%) had DCIS + LCIS. At median follow-up of 7.2 (range 0–17) years, 307 patients had a subsequent first breast event; 207 IBTR and 100 CBC. The 10-year cumulative incidence of IBTR was similar in both groups: 15.0% vs. 14.2% (log-rank, p = 0.8) for DCIS + LCIS vs. DCIS, respectively. The 10-year cumulative incidence of CBC was greater in the DCIS + LCIS group: 10.9% vs. 6.1% for DCIS (log-rank, p

The efficacy of chemoprevention for breast cancer risk reduction has been demonstrated in randomized controlled trials; however, use remains low. We sought to determine whether uptake differed by risk factors, and to identify reasons for refusal and termination. Women seen in a high-risk clinic from October 2014 to June 2017 considered eligible for chemoprevention (history of lobular carcinoma in situ, atypia, family history of breast/ovarian cancer, genetic mutation, or history of chest wall radiation) were retrospectively identified. Breast cancer risk factors were compared among those with and without chemoprevention use, and compliance was noted. Overall, 1506 women were identified, 24% with prior/current chemoprevention use. Women ≥ 50 years of age were more likely to use chemoprevention than women

Background: Low uptake and poor adherence to oral drugs for breast cancer prevention and ductal carcinoma in situ has led to an interest in local routes of delivery with the intent of decreasing systemic exposure and reducing toxicity. LTT has emerged as a possible alternative; previous studies have shown selectively higher concentrations in the breast than in the serum with this delivery route. A question related to LTT is whether or not the drug will permeate and distribute throughout the breast, as is expected with oral delivery. Methods: We conducted a double-blind study of oral versus LTT delivery of the selective progesterone receptor modulator, telapristone acetate (TPA), in a presurgical window setting, enrolling 82 women planning therapeutic or prophylactic mastectomy. We randomized 67 women 1:1, to oral TPA 12 mg daily, or gel TPA applied to both breasts daily (12 mg/breast), for 4 weeks ±1 week. Mastectomy specimens were sampled at 5 non-tumor locations as well as the tumor and lymph node when available. Samples were split in two: drug concentration (conc.) assay using LC-MS/MS and histological evaluation of tissue composition (fat, fibrous stroma, epithelium). The primary endpoint was mean drug conc. across all breast locations (anticipating that the gel would deliver a mean concentration that was >50% of the mean in the oral group). A secondary endpoint was the drug distribution pattern across the breast, expecting that the distribution would be similar. The tumor sample was saved for biomarker assays related to TPA action; these are ongoing, for a pre-planned pooled analysis of data with NCT01800422 (reported in SABCS abstract 851863). Results: Of 63 evaluable women (33 oral and 30 gel group), 27 had unilateral and 36 had bilateral mastectomy. The mean drug conc. in the oral group was 166.3 ng/G (SE 11.7), and in the gel group was 10.6 ng/G (SE 10.8), (p Conclusions: The gel formulation of TPA did not permeate the skin well. However, the drug delivered to the breast was distributed throughout the breast, similar to the oral delivery route, with the highest concentration in the deep central location. These drug distribution data are novel; drug distribution at multiple locations throughout the breast has not previously been shown. Further work is needed to understand breast distribution with formulations known to have good dermal permeation. Citation Format: Lee O, Pilewskie M, Xu Y, Benante K, Blanco L, Helenowski I, Tull MB, Muzzio M, Jovanovic B, Karlan S, Hansen N, Bethke K, Kulkarni S, Perloff M, Dimond EP, Heckman-Stoddard BM, Khan SA. Local transdermal therapy (LTT): Drug permeation and distribution of telapristone acetate (TPA) in a pre-surgical window study of women undergoing mastectomy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-12.

Background: LCIS is considered a risk factor for bilateral breast cancer, but the effect of LCIS diagnosed concurrently with DCIS is not known. We sought to compare CBC and ipsilateral breast tumor recurrence (IBTR) rates in women with DCIS with and without synchronous LCIS treated with breast conserving surgery (BCS). Methods: A prospectively maintained database of DCIS patients undergoing BCS from 2000-2011 was used to identify women with a contralateral breast at risk. Patients with synchronous ipsilateral LCIS found at core needle biopsy or surgical excision were included in the “DCIS + LCIS” group; those with contralateral or bilateral LCIS were excluded. Associations of patient, tumor, and treatment factors with CBC and IBTR were evaluated using logistic regression. Results: Of the 1888 patients identified, 1475 (78%) had DCIS only and 413 (22%) had DCIS with synchronous LCIS. Median follow-up was 7.5 years (range 0-17 years). 305 patients had a subsequent breast event; 216 IBTR and 89 CBC. The 5 and 10-year cumulative incidence of IBTR was similar in both groups: 6.3% and 14.4% for DCIS only, compared with 5.9% and 14.0% for DCIS + LCIS (p = 0.94), respectively. The 5 and 10-year cumulative incidence of CBC was significantly greater in the DCIS + LCIS group: 5.7% and 10.0%, compared with 2.4% and 5.0% for DCIS only (p < 0.001). Table 1 summarizes uni-and multi-variable analyses of risk factors associated with CBC and IBTR among women with DCIS treated with BCS. After adjustment for other factors, CBC risk was more than 2-fold higher in the DCIS + LCIS group compared with the DCIS only group (HR 2.37, 95% CI 1.54-3.65, p < 0.001). There was no difference in IBTR risk based on presence of synchronous LCIS. Younger age and receipt of endocrine therapy were significantly associated with decreased risk of CBC. Table 1:Risk factors associated with CBC and IBTR in patients with DCIS treated with BCS Univariate Analysis Multivariate Analysis Hazard Ratio (95% CI) Hazard Ratio (95% CI) CBC IBTR CBC IBTRAge (continuous)1.02 (1.01-1.04) *0.99 (0.98-1.0)1.02 (1.0-1.04) *0.99 (0.97-1.0) *Presentation Radiologic1111Clinical0.36 (0.11-1.14)1.56 (1.05-2.3) *0.41 (0.13-1.31)1.67 (1.12-2.47) *Family history Yes1.32 (0.87-2.01)1.0 (0.76-1.32)1.33 (0.87-2.03)1.03 (0.78-1.35)Grade Low1111Intermediate/high1.83 (1.0-3.37)1.32 (0.93-1.88)1.74 (0.92-3.29)1.62 (1.11-2.35) *Radiation Yes1.16 (0.75-1.8)0.7 (0.54-0.92) *1.14 (0.71-1.82)0.64 (0.48-0.86) *Endocrine Therapy Yes0.43 (0.23-0.81) *0.51 (0.35-0.74) *0.42 (0.22-0.8) *0.53 (0.36-0.77) *DCIS group DCIS only1111DCIS + LCIS2.28 (1.49-3.5) *0.99 (0.71-1.36)2.37 (1.54-3.65) *0.99 (0.71-1.37)* p < 0.05 Conclusions: LCIS diagnosed concurrently with DCIS is not associated with IBTR, but increases the risk of CBC two-fold. Endocrine therapy should be considered both for the index DCIS and for prevention of subsequent CBC. Citation Format: Miller ME, Muhsen S, Zabor EC, Flynn J, Olcese C, Giri D, Van Zee KJ, Pilewskie M. Risk of contralateral breast cancer (CBC) in women with ductal carcinoma in situ (DCIS) with and without and synchronous lobular carcinoma in situ (LCIS) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-01.

BACKGROUND: BRCA mutation carriers have an elevated lifetime breast cancer risk and remain at risk for interval cancer development. We sought to compare BRCA mutation carriers with screen-detected versus interval breast cancers. METHODS: Women with a known BRCA mutation prior to a breast cancer diagnosis were identified. Clinical and pathologic factors, and imaging within 18 months of diagnosis were compared among screen-detected versus interval cancers. Interval cancers were those detected by physical exam among women undergoing regular screening. RESULTS: Of 124 breast cancers, 92 were screen and 22 clinically detected, of which 11 were interval cancers among regular screeners, and 10 were incidentally found on prophylactic mastectomy. Women with interval cancers were younger, had lower body mass indexes, and were more likely to be Black than those with screen-detected cancers (p

BACKGROUND AND OBJECTIVES: Women with unilateral early-stage breast cancer are increasingly choosing contralateral prophylactic mastectomy (CPM) despite the absence of survival benefits and increased risk of surgical complications. Data are lacking on whether this trend extends to women with clinically locally advanced non-metastatic (cT4M0) cancer. This study aims to estimate national CPM trends in women with unilateral cT4M0 breast cancer. METHODS: Women aged ≥ 18 years, who underwent mastectomy during 2004–2014 for unilateral cT4M0 breast cancer were identified using the National Cancer Database and grouped as all locally advanced (T4), chest wall invasion, skin nodule/ulceration, or both (T4abc), and inflammatory (T4d) cancer. Poisson regression for trends and logistic modeling for predictors of CPM were performed. RESULTS: Of 23,943 women, 41% had T4abc disease and 35% T4d. Cumulative CPM rates were 15%, 23% and 18%, for the T4abc, T4d and all T4 groups, respectively. Trend analysis revealed a significant upsurge in CPM demonstrating 12% annual growth for T4abc tumors, 8% for T4d and 9% for all T4 (all P < 0.001). CONCLUSIONS: Increasing numbers of women with unilateral cT4M0 breast cancer, are undergoing CPM. This rising trend warrants further research to understand stakeholders’ preferences in surgical decision-making for women with locally advanced breast cancer.

Background Despite increasing numbers of women with unilateral breast cancer undergoing CPM, quantitative evidence of all stakeholder preferences regarding CPM is lacking, particularly for healthy volunteers. Conjoint analysis, a marketing tool, can be used to quantify tradeoffs surrounding CPM. Study design The objective of this study was to quantify preferences for aspects of contralateral prophylactic mastectomy (CPM) decision-making process among key stakeholders. Healthy volunteers, women with cancer (WwCa), surgical oncologists, and plastic surgeons were surveyed with the same conjoint simulation exercise. Respondents chose between either single (SM) or double (DM) mastectomy under varying recurrence and complication rates, surveillance, and symmetry conditions. Hierarchical Bayesian models calculated partworth utilities and importance scores. Results Overall, 1,244 respondents participated. The top 3 important factors for all stakeholders were surgical complication rates after DM, type of surgery (SM vs DM) independent of other variables, and 10-year future contralateral cancer risk after SM. HV and surgeons placed greatest importance on high rates of surgical complications after DM. WwCa preferred DM, regardless of complication risk or low rates of a 10-year future cancer episode after SM. Surgical oncologists strongly preferred SM and were more accepting of future cancer risk of 3% or 10% than other stakeholders. Symmetry and need for surveillance were least important factors for all stakeholders. Conclusions The threshold of acceptability for future cancer episodes and risk tolerance for complications varies by stakeholder, with a profound influence upon WwCA. Current findings suggest room for improved provider and patient alignment through behavioral techniques, such as framing, meanwhile highlighting changes in risk perception after a breast cancer diagnosis.

Simple Summary Breast cancer survivors are at risk for recurrence, and the early detection of recurrence improves survival. Therefore, imaging surveillance is performed for women who have breast-conserving surgery. The aim of our retrospective study was to compare routine mammography with contrast-enhanced mammography in the screening (asymptomatic) post-treatment setting. We confirmed that when screening women with breast conservation surgery, contrast-enhanced mammography had a higher cancer detection rate (15.4/1000) and positive predictive value of biopsies (42.9%) than full-field digital mammography (6.2/1000 and 37.5%, respectively). Abstract To investigate the value of contrast-enhanced mammography (CEM) compared to full-field digital mammography (FFDM) in screening breast cancer patients after breast-conserving surgery (BCS), this Health Insurance Portability and Accountability Act-compliant, institutional review board-approved retrospective, single-institution study included 971 CEM exams in 541 asymptomatic patients treated with BCS who underwent screening CEM between January 2013 and November 2018. Histopathology, or at least a one-year follow-up, was used as the standard of reference. Twenty-one of 541 patients (3.9%) were diagnosed with ipsi- or contralateral breast cancer: six (28.6%) cancers were seen with low-energy images (equivalent to FFDM), an additional nine (42.9%) cancers were detected only on iodine (contrast-enhanced) images, and six interval cancers were identified within 365 days of a negative screening CEM. Of the 10 ipsilateral cancers detected on CEM, four were detected on low-energy images (40%). Of the five contralateral cancers detected on CEM, two were detected on low-energy images (40%). Overall, the cancer detection rate (CDR) for CEM was 15.4/1000 (15/971), and the positive predictive value (PPV3) of the biopsies performed was 42.9% (15/35). For findings seen on low-energy images, with or without contrast, the CDR was 6.2/1000 (6/971), and the PPV3 of the biopsies performed was 37.5% (6/16). In the post-BCS screening setting, CEM has a higher CDR than FFDM.

Neoadjuvant endocrine therapy (NET) is effective in downstaging large hormone receptor-positive (HR+) breast cancers and increasing rates of breast-conserving surgery (BCS), but data regarding nodal pathologic complete response (pCR) are sparse. We reported nodal and breast downstaging rates with NET, and compared axillary response rates following NET and neoadjuvant chemotherapy (NAC). Consecutive stage I–III breast cancer patients treated with NET and surgery from January 2009 to December 2019 were identified from a prospectively maintained database. Nodal pCR rates were compared between biopsy-proven node-positive patients treated with NET, and HR+/HER2- patients treated with NAC from November 2013 to July 2019. 127 cancers treated with NET and 338 with NAC were included. NET recipients were older, more likely to have lobular and lower-grade tumors, and higher HR expression. With NET, the nodal pCR rate was 11% (4/38) of biopsy-proven cases, and the breast pCR rate was 1.6% (2/126). Nodal-dowstaging rates with NET and NAC were not significantly different (11% vs 18%; P = 0.37). Patients achieving nodal pCR with NET versus NAC were older (median age 70 vs 50, P = 0.004) and had greater progesterone receptor (PR) expression (85% vs 13%, P = 0.031), respectively. Of patients not candidates for BCS due to a large tumor relative to breast size, 36/47 (77%) became BCS-eligible with NET (median PR expression 55% vs 5% in those remaining ineligible, P

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.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.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.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.

Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes.A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores.Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26 kg/mIn women with newly diagnosed breast cancer, increasing insulin resistance is associated with a higher recurrence score; however, this association was not present in Black women. This lack of association may be due to the small number of Black women in the cohort, or possibly a reflection of a different biological disease process of the patient's tumor.

The appropriate negative margin width for women undergoing breast-conserving surgery for both ductal carcinoma in situ (DCIS) and invasive carcinoma is controversial. This review examines the available data on the margin status for invasive breast cancer and DCIS, and highlights the similarities and differences in tumor biology and standard treatments that affect the local recurrence (LR) risk and, therefore, the optimal surgical margin. Consensus guidelines support a negative margin, defined as no ink on tumor, for invasive carcinoma treated with breast-conserving therapy. Because of differences in the growth pattern and utilization of systemic therapy, a margin of 2 mm has been found to minimize the LR risk for women with DCIS undergoing lumpectomy and radiation therapy (RT). Wider negative margins do not improve local control for DCIS or invasive carcinoma when they are treated with lumpectomy and RT. Re-excision for negative margins should be individualized, and the routine practice of performing additional surgery to obtain a wider negative margin is not supported by the literature. Cancer 2018;124:1335-41. © 2018 American Cancer Society.

Background: Four prospective multi-institutional trials have demonstrated that clinically node-positive patients (cN1) who receive neoadjuvant therapy (NAC) and convert to cN0 can be reliably staged with sentinel lymph node biopsy (SLNB) with false-negative rates (FNRs) of < 10%, when ≥ 3 SLNs are retrieved. Since study patients all had axillary lymph node dissection (ALND), the rate of axillary recurrence after SLNB alone is unknown. Of concern is the possibility that residual chemotherapy-resistant axillary disease could lead to higher recurrence rates than seen in the primary surgery setting for cN0 patients where SLN FNRs of 5-10% result in axillary recurrence in < 1% of cases. Here we report regional recurrence rates in a prospectively defined cohort of cN1 patients receiving NAC, followed by a negative SLNB using a standardized technique, and no further axillary surgery. Methods: From 06/2014 to 02/2019, patients with cT1-3 biopsy-proven cN1 breast cancer who received NAC and converted to cN0 by physical exam were prospectively managed with SLNB with dual tracer mapping and omission of ALND if ≥ 3 SLNs were pathologically negative. Nodes were not routinely clipped, and retrieval of clipped metastatic nodes was not required. Pathologically negative SLNs were defined as the absence of any metastases including isolated tumor cells. Results: Of 610 cN1 patients treated with NAC, 555 (91%) converted to cN0 and had SLNB; 234 (42%) had ≥ 3 negative SLNs and were treated with SLNB alone. Median patient age was 49 years and median tumor size at presentation was 3 cm; 61% were HER2+ and 18% triple negative. Most (91%) received doxorubicin-based NAC and 88% received adjuvant radiotherapy (RT), with 80% (n = 164) of RT patients receiving nodal RT (Table). At a median follow-up of 35 months, there was only 1 (0.4%) axillary recurrence for the entire cohort, synchronous with a breast recurrence, in a patient who refused RT. Among patients who received RT (n = 205), there were no axillary recurrences. The 4-year rate of distant recurrence for all patients was 6.1% (95% CI, 3.4-10.7%) and 4-year overall survival was 93.9% (95% CI, 87.6-97.1%). Conclusion: In cN1 patients treated with NAC, rates of axillary recurrence in patients with ≥ 3 pathologically negative SLNs treated with SLNB alone were low, without routine nodal clipping. Although further follow-up is needed, multiple studies have shown that nodal recurrence is an early event, particularly in HER2+ and triple negative patients, who comprised the majority of the population. Our findings support omitting ALND in cN1 patients after NAC when the SLNs are negative using an optimal SLNB technique. Table. Patient PopulationOverall cohort (n = 234)Age, years (median, IQR)49 (40, 58)Tumor size at presentation, cm (median, IQR)3.0 (2.2, 5.0)Number SLNs retrieved (median, IQR)4 (3, 5)Palpable nodes at presentation (n, %)179 (76%)HistologyDuctal211 (90%)Lobular and mixed7 (3%)Micropapillary and mixed10 (4%)Other3 (1%)Occult3 (1%)DifferentiationWell1 (0.5%)Moderate36 (15%)Poor196 (84%)Unknown1 (0.5%)Receptor StatusHR+/HER2-47 (20%)HR+/HER2+80 (34%)HR-/HER2+64 (27%)HR-/HER2-43 (18%)Breast SurgeryBCS118 (50%)Mastectomy116 (50%)Breast pCR¥Yes161 (70%)No70 (30%)NAC regimenAC-T197 (84%)AC-T + carbo15 (6.4%)TC8 (3.4%)Other14 (6%)Neoadjuvant anti-HER2 treatmentHP (dual-therapy)144 (100%)Adjuvant RTYes205 (88%)No*29 (12%)¥3 patients had occult primary breast cancer and were not included in breast pCR calculation; *6/29 patients who did not receive RT enrolled in NSABP B-51 Citation Format: Andrea V Barrio, Giacomo Montagna, Anita Mamtani, Varadan Sevilimedu, Hiram S Cody, III, Mahmoud El-Tamer, Mary L Gemignani, Alexandra S Heerdt, Tracy-Ann Moo, Melissa Pilewskie, George Plitas, Lisa Sclafani, Kimberly J Van Zee, Monica Morrow. Axillary recurrence is a rare event in node-positive patients. treated with sentinel node biopsy alone after neoadjuvant chemotherapy: Results of a prospective study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD4-05.

560 Background: Metabolic syndrome (MS) is associated with worse breast cancer prognosis. Black women have higher rates of advanced breast cancer, as well as MS, diabetes and obesity. As socioeconomic status is associated with MS, we asked whether the subjective perception of social status (SSS), might influence this association in black and white women with a new breast cancer (BC) diagnosis. Methods: We surveyed, obtained serum and conducted anthropometric measures of 1206 women with a new BC diagnosis. Triglycerides, systolic blood pressure (SBP), waist circumference (cm), HDL and glucose were used to calculate a severity index of MS (MS-Zscore: mean=0; sd=1). Women reported their SSS on the 10 rung McArthur US social status ladder, their household income, education attained, diet quality (5 point scale), and exercise measured with metabolic equivalents (METS). Data were analyzed with multivariable generalized linear models. Missing data were imputed with multiple imputation. Results: Average age was 58 yrs of 295 black and 911 white women. BC stage > II was in 11.6% of black and 2.4% of white women. On average black women had higher BMI (31.5 vs 26.6; pth %ile), and less likely to graduate college (30.3% vs 70.4%). MSZ-score was positively associated with age (.02 per year; p

BACKGROUND The current study was conducted to examine the association between ipsilateral breast tumor recurrence (IBTR) and the timing of radiotherapy (RT) in women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS). METHODS Women with DCIS who were treated with BCS and RT from 1980 through 2010 were identified from a prospectively maintained database. IBTR rates, measured from the time of RT completion, were compared between those who initiated RT ≤8 weeks, >8 to 12 weeks, and >12 weeks after the completion of surgery. The association between RT timing and IBTR was evaluated by Kaplan-Meier and log-rank analyses; Cox modeling was used for multivariable analysis. RESULTS A total of 1323 women met the inclusion criteria. The median follow-up was 6.6 years, with 311 patients followed for ≥10 years. A total of 126 IBTR events occurred. Patients were categorized by RT timing: 806 patients (61%) with timing of ≤8 weeks, 386 patients (29%) with timing of >8 to 12 weeks, and 131 patients (10%) with timing >12 weeks. The 5-year and 10-year IBTR rates were 5.8% and 13.0%, respectively, for RT starting ≤8 weeks after surgery; 3.8% and 7.6%, respectively, for RT starting >8 to 12 weeks after surgery; and 8.8% and 23.0%, respectively, for an RT delay >12 weeks after surgery (P = .004). On multivariable analysis, menopause (hazard ratio [HR], 0.54; P = .0009) and endocrine therapy (HR, 0.45; P = .002) were found to be protective against IBTR, whereas a delay in RT >12 weeks compared with ≤8 weeks was associated with a higher risk of IBTR (HR, 1.92; P = .014). There was no difference in IBTR noted between RT initiation at ≤8 weeks and initiation at >8 to 12 weeks after BCS (P = .3). CONCLUSIONS A delay in RT >12 weeks is associated with a significantly higher risk of IBTR in women undergoing BCS for DCIS. Efforts should be made to avoid delays in starting RT to minimize the risk of disease recurrence. Cancer 2018;124:46-54. © 2017 American Cancer Society.

Women with a BRCA mutation have significantly elevated breast cancer risk, which can be reduced by >90% with bilateral prophylactic mastectomy (BPM). We sought to compare a cohort of BRCA mutation carriers choosing BPM versus breast surveillance to better elucidate factors that may impact decision making. Women with a BRCA mutation were retrospectively identified from a prospectively maintained database. The surveillance cohort (n = 313) consisted of women seen in a high-risk clinic between 2014 and 2016, while the surgery cohort (n = 142) consisted of women who underwent BPM between 2010 and 2016. Clinical and familial factors were compared between the groups. Women choosing BPM were more likely to have a BRCA1 than BRCA2 mutation compared with the surveillance group (57 vs. 45%, p = 0.02) and were less likely to have a personal history of ovarian cancer (10 vs. 20%, p = 0.01). Furthermore, women undergoing BPM were more likely to be married (78 vs. 62%, p = 0.01), to have more children (median 2 vs. 1, p

The phrase “high-risk for breast cancer” is used to identify various groups at elevated cancer risk, and the appropriate surveillance and risk-reducing strategies differ based on the etiology of risk. Here, we review the utility of patient-reported data to capture women with modifiable lifestyle risk factors and those suitable for genetic counseling referral. Patient-reported data from a web-based survey were used to capture personal history, multi-generational family history, and lifestyle factors (body mass index, alcohol consumption, physical activity). Responses were tabulated, and percentage of patients who met criteria for possible intervention calculated. 1277 women completed the survey from October 2014 to December 2015. Women were considered high risk for a combination of the following: family history of breast and/or ovarian cancer (77%), history of atypical hyperplasia or lobular carcinoma in situ (35%), known breast cancer-related gene mutation (11%). Based on self-reported data, 65% qualified for genetic evaluation but 40% reporting no prior testing. Only half of the population met national physical activity recommendations, nearly 40% were overweight/obese, and 18% reported consuming ≥1 alcoholic beverage per day. Among women followed in a high-risk breast surveillance program, there is considerable opportunity for improved genetic referral and awareness of modifiable lifestyle factors based on self-reported data as 60% of respondents reported a possible area for intervention. While risk reduction associated with lifestyle changes is modest in comparison to chemoprevention or surgery, such changes are practically without risk, minimally expensive, and provide innumerable secondary health benefits.

Identifying DCIS patients at low risk for disease progression could obviate need for standard therapy. The LORIS (surgery versus active monitoring for low-risk DCIS) trial is studying the safety of monitoring low-risk DCIS, although ipsilateral breast tumor recurrence (IBTR) rates in patients meeting enrollment criteria after complete surgical excision are unknown. Women with pure DCIS treated with breast-conserving surgery (BCS) with/without radiation therapy (RT) from 1/1996–1/2011 were included from a prospectively maintained database. IBTR rates were compared between those who did and did not meet LORIS eligibility criteria (age ≥ 46 years, screen-detected calcifications, nipple discharge absence, minimal family history, non-high-grade DCIS) after complete surgical excision. A total of 2394 women were identified; 401 met LORIS criteria. Median follow-up was 5.9 years; 431 had ≥10 years follow-up. LORIS cohort median age was 61 years (range 46–86 years); 207 (52 %) underwent RT, 79 (20 %) received endocrine therapy. Of 401 patients, 24 experienced an IBTR. Overall 10-year IBTR rates were 10.3 % (LORIS) versus 15.4 % (non-LORIS) (p = 0.08); without RT, 12.1 versus 21.4 %, respectively (p = 0.06). The 10-year invasive-IBTR rates for women meeting LORIS criteria were: 5.3 % BCS overall, 6.0 % without RT. Women meeting LORIS criteria (after complete surgical excision) are at somewhat lower risk for IBTR. Among such women undergoing excision without RT, the 10-year invasive-IBTR rate was 6 %. Given that approximately 20 % of women with core biopsy-proven non-high-grade DCIS have invasive cancer at excision, women managed without excision would be expected to incur higher invasive cancer rates. Additional criteria are needed to identify women not requiring intervention for DCIS.

BACKGROUND/OBJECTIVE: The efficacy of chemoprevention for breast cancer risk reduction has been demonstrated in randomized controlled trials; however, use remains low. We sought to determine whether uptake differed by risk factors, and identify reasons for refusal and termination. METHODS: Women seen in a high-risk clinic from 10/2014-6/2017 considered eligible for chemoprevention, (history of LCIS, atypia, family history of breast/ovarian cancer, genetic mutation, or history of chest wall radiation) were retrospectively identified. Breast cancer risk factors were compared among those with and without chemoprevention use, and compliance noted. RESULTS: 1,506 women were identified, 24% with prior/current chemoprevention use. Women ≥50 years of age were more likely to use chemoprevention than women

More than one-third of American adults are obese, and an elevated body mass index (BMI) is postulated to reduce the sensitivity of the clinical evaluation of the axilla. Clinical nodal examination is important in allocating breast cancer patients to appropriate axillary management. This study sought to determine whether BMI influences the rate of nodal positivity in women designated clinically as node-negative (cN0) by physical examination. Breast cancer patients deemed cN0 who underwent sentinel lymph node biopsy (SLNB) from February 2006 to December 2011 were identified from a prospectively maintained database. Clinicopathologic features including BMI and axillary surgery results were recorded and compared among pathologically node-negative and node-positive patients. Overall, 5142 cN0 patients underwent 5262 SLNB procedures during the study period. Nearly one-third of the patients (28 %) were obese (BMI, >30 kg/m2). A positive SLN was identified in 25 % of the patients, and 84 % proceeded to axillary lymph node dissection. Predictors of SLN positivity included younger age, larger tumor size, high nuclear grade, multifocality, and lymphovascular invasion. An increased BMI did not correlate with a higher likelihood of SLN positivity (p = 0.6). The likelihood of cN0 patients having a high burden of axillary metastases (>3 positive nodes) was 4 % overall and, similarly, did not differ according to BMI (p = 0.4). Elevated BMI was not associated with a higher likelihood of SLN positivity or heavy nodal disease burden among women staged as cN0 by physical exam. These findings indicate that physical examination is appropriate and sufficient for preoperative axillary evaluation of women undergoing initial surgery regardless of patient BMI.

The Surgery Versus Active Monitoring for Low-Risk DCIS (LORIS) trial is studying the safety of monitoring core-biopsy diagnosed low-risk ductal carcinoma in situ (DCIS) without excision. We sought to determine the incidence and characteristics of synchronous invasive carcinoma found in LORIS-eligible women who underwent excision, as this knowledge is essential in assessing the safety of observation alone. Women meeting LORIS eligibility criteria (age ≥46 years, screen-detected calcifications, non-high-grade DCIS diagnosed by core biopsy, absence of nipple discharge, or strong family history of breast cancer) who underwent surgical excision from 2009 to 2012 were identified. Histologic findings of excision specimens were reviewed. Overall, 296 LORIS-eligible cases were identified; 58 (20 %) had invasive carcinoma on final pathology (90 % invasive ductal, 78 % >1 mm in size, 21 % high grade, 3 % triple negative, 9 % HER2 amplified). Of these, 18 (31 %) were pT1b or larger and 3 (5 %) were pN1. Among eligible upgraded cases, 90 % received radiation, 89 % received endocrine therapy, and 18 % were recommended chemotherapy. Women upgraded to invasive carcinoma were more likely to have intermediate-grade DCIS on core biopsy and to have undergone mastectomy. Among LORIS-eligible women, 20 % had invasive carcinoma at surgical excision that was heterogeneous in grade, size, and receptor status. Information gained from surgical excision influenced receipt of adjuvant radiation and endocrine therapy in most patients, and indicated benefit from chemotherapy in 18 % of patients. Surgical excision is warranted until additional risk stratification is available to identify a cohort of DCIS patients at lower risk for clinically significant synchronous invasive carcinoma.

The American College of Surgeons Oncology Group Z0011 trial demonstrated the safety of omitting axillary lymph node dissection (ALND) for women with fewer than three positive sentinel lymph nodes (SLNs) who are undergoing breast-conservation therapy (BCT). Because most of the women were postmenopausal with estrogen receptor (ER) positive cancers, applicability of ALND for younger patients and those with triple-negative (TN) or human epidermal growth factor receptor 2 (HER2) overexpressing (HER2+) tumors remains controversial.From August 2010 to December 2015, patients undergoing BCT for cT1-2N0 disease and found to have positive SLNs were prospectively followed. Axillary lymph node dissection was indicated for more than two positive SLNs or gross extracapsular extension. Clinicopathologic characteristics, axillary surgery, nodal burden, and outcomes were compared between the high-risk patients (TN, HER2+, or age 50 years) and the remaining patients, termed average risk patients.Among 701 consecutive patients, 242 (35 %) were high risk: 31 (13 %) with TN, 48 (20 %) with HER2+, 130 (54 %) with age less than 50 years, and 33 (14 %) with more than one high-risk feature. The remaining 459 patients (65 %) were average risk. The high-risk patients were younger, had higher-grade tumors (p 0.0001), and more often had abnormal nodes imaged (p = 0.02). In this study, SLNB alone was performed for 85 % high-risk versus 82 % average-risk cases (p = 0.39). A median of four versus three SLNs were excised (p = 0.04), and both groups had a median of one positive SLN. Additional positive nodes at ALND were found in 62 % high-risk patients versus 65 % average-risk patients (p = 0.8), with a median of three positive nodes in both groups. During a median follow-up period of 31 months, no patients experienced isolated axillary recurrences.Axillary lymph node dissection was no more likely to be indicated for high-risk patients. For patients undergoing ALND, the nodal burden was similar. For patients otherwise meeting the American College of Surgeons Oncology Group (ACOSOG) Z0011 clinical eligibility criteria, ALND is not indicated on the basis of age or subtype.

Sentinel lymph node biopsy (SLNB) is recommended when mastectomy is performed for ductal carcinoma in situ (DCIS). The role of SLNB for women with DCIS who undergo mastectomy following one or more attempts at breast-conserving surgery (BCS) is uncertain. We examined the upgrade rate and SLNB yield in women who converted to mastectomy after one or more attempts at BCS for DCIS. All patients who underwent one or more attempts at BCS prior to conversion to mastectomy with SLNB for DCIS were identified. Margin status as the indication for mastectomy was confirmed, and comparisons were made between patients with/without upgrade on final pathology. From February 2006 to November 2012, a total of 233 patients underwent completion mastectomy following one or more attempts at BCS for positive/close margins (median age 50 years; range 34–84). The median number of BCS attempts was 1 (range 1–4). Overall, 20 (9 %) patients were upgraded on final pathology; 15 (6 %) stage I, and 5 (3 %) stage II (three micrometastasis, two macrometastasis). In two of five cases with a positive SLN, invasive carcinoma was not identified in the mastectomy specimen. The only factor associated with any upgrade was the presence of micropapillary DCIS (80 vs. 55 %, with and without upgrade; p = 0.03). In this cohort of patients with DCIS who converted to mastectomy for positive/close margins after one or more attempts at BCS, 18 (8 %) would have required second-stage axillary surgery had an SLNB not been performed, and in two (1 %) patients, the SLN provided the only evidence of invasion. These findings support the recommendation for SLNB at the time of completion mastectomy.

Purpose The increased breast cancer risk conferred by a diagnosis of lobular carcinoma in situ (LCIS) is poorly understood. Here, we review our 29-year longitudinal experience with LCIS to evaluate factors associated with breast cancer risk. Patients and Methods Patients participating in surveillance after an LCIS diagnosis are observed in a prospectively maintained database. Comparisons were made among women choosing surveillance, with or without chemoprevention, and those undergoing bilateral prophylactic mastectomies between 1980 and 2009. Results One thousand sixty patients with LCIS without concurrent breast cancer were identified. Median age at LCIS diagnosis was 50 years (range, 27 to 83 years). Fifty-six patients (5%) underwent bilateral prophylactic mastectomy; 1,004 chose surveillance with (n = 173) or without (n = 831) chemoprevention. At a median follow-up of 81 months (range, 6 to 368 months), 150 patients developed 168 breast cancers (63% ipsilateral, 25% contralateral, 12% bilateral), with no dominant histology (ductal carcinoma in situ, 35%; infiltrating ductal carcinoma, 29%; infiltrating lobular carcinoma, 27%; other, 9%). Breast cancer incidence was significantly reduced in women taking chemoprevention (10-year cumulative risk: 7% with chemoprevention; 21% with no chemoprevention; P < .001). In multivariable analysis, chemoprevention was the only clinical factor associated with breast cancer risk (hazard ratio, 0.27; 95% CI, 0.15 to 0.50). In a subgroup nested case-control analysis, volume of disease, which was defined as the ratio of slides with LCIS to total number of slides reviewed, was also associated with breast cancer development (P = .008). Conclusion We observed a 2% annual incidence of breast cancer among women with LCIS. Common clinical factors used for risk prediction, including age and family history, were not associated with breast cancer risk. The lower breast cancer incidence in women opting for chemoprevention highlights the potential for risk reduction in this population.