Participation in a High-Risk Program Is Associated with a Diagnosis of Earlier-Stage Disease Among Women at Increased Risk for Breast Cancer Development.

BACKGROUND: High-risk programs provide recommendations for surveillance/risk reduction for women at elevated risk for breast cancer development. This study evaluated the impact of high-risk surveillance program participation on clinicopathologic breast cancer features at the time of diagnosis. METHODS: Women followed in the authors' high-risk program (high-risk cohort [HRC]) with a diagnosis of breast cancer from January 2015 to June 2021 were identified and compared with the general population of women undergoing breast cancer surgery at Memorial Sloan Kettering Cancer Center (MSK; general cohort [GC]) during the same period. Patient and tumor factors were collected. Clinicopathologic features were compared between the two cohorts and in a subset of women with a family history of known BRCA mutation. RESULTS: The study compared 255 women in the HRC with 9342 women in the GC. The HRC patients were slightly older and more likely to be white and have family history than the GC patients. The HRC patients also were more likely to present with DCIS (41 % vs 23 %; p < 0.001), to have smaller invasive tumors (pT1: 100 % vs 77 %; p < 0.001), and to be pN0 (95 % vs 81 %; p < 0.001). The HRC patients had more invasive triple-negative tumors (p = 0.01) and underwent less axillary surgery (p < 0.001), systemic therapy (p < 0.001), and radiotherapy (p = 0.002). Among those with a known BRCA mutation, significantly more women in the HRC underwent screening mammography (75 % vs 40 %; p < 0.001) or magnetic resonance imaging (MRI: 82 % vs 9.9 %; p < 0.001) in the 12 months before diagnosis. CONCLUSIONS: Women followed in a high-risk screening program have disease diagnosed at an earlier stage and therefore require less-intensive breast cancer treatment than women presenting to a cancer center at the time of diagnosis. Identification of high-risk women and implementation of increased surveillance protocols are vital to improving outcomes.

Regional Blocks Benefit Patients Undergoing Bilateral Mastectomy with Immediate Implant-Based Reconstruction, Even After Discharge.

BACKGROUND: There is limited evidence that regional anesthesia reduces pain in patients undergoing mastectomy with immediate implant-based reconstruction. We sought to determine whether regional blocks reduce opioid consumption and improve post-discharge patient-reported pain in this population. METHODS: We retrospectively reviewed patients who underwent bilateral mastectomy with immediate implant-based reconstruction with and without a regional block. We tested for differences in opioid consumption by block receipt using multivariable ordinal regression, and also assessed routinely collected patient-reported outcomes (PROs) for 10 days postoperatively and tested the association between block receipt and moderate or greater pain. RESULTS: Of 754 patients, 89% received a block. Non-block patients had an increase in the odds of requiring a higher quartile of postoperative opioids. Among block patients, the estimated probability of being in the lowest quartile of opioids required was 25%, compared with 15% for non-block patients. Odds of patient-reported moderate or greater pain after discharge was 0.54 times lower in block patients than non-block patients (p = 0.025). Block patients had a 49% risk of moderate or greater pain compared with 64% in non-block patients on postoperative day 5. There was no indication of any reason for these differences other than a causal effect of the block. CONCLUSION: Receipt of a regional block resulted in reduced opioid use and lower risk of self-reported moderate and higher pain after discharge in bilateral mastectomy with immediate implant-based reconstruction patients. Our use of PROs suggests that the analgesic effects of blocks persist after discharge, beyond the expected duration of a 'single shot' block.

Upgrade Rates and Breast Cancer Development Among Germline Pathogenic Variant Carriers with High-Risk Breast Lesions.

BACKGROUND: High-risk lesions (HRL) of the breast are risk factors for future breast cancer development and may be associated with a concurrent underlying malignancy when identified on needle biopsy; however, there are few data evaluating HRLs in carriers of germline pathogenic variants (PVs) in breast cancer predisposition genes. METHODS: We identified patients from two institutions with germline PVs in high- and moderate-penetrance breast cancer predisposition genes and an HRL in an intact breast, including atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and lobular neoplasia (LN). We calculated upgrade rates at surgical excision and used Kaplan-Meier methods to characterize 3-year breast cancer risk in patients without upgrade. RESULTS: Of 117 lesions in 105 patients, 65 (55.6%) were ADH, 48 (41.0%) were LN, and 4 (3.4%) were FEA. Most PVs (83.8%) were in the BRCA1/2, CHEK2 and ATM genes. ADH and FEA were excised in most cases (87.1%), with upgrade rates of 11.8% (95% confidence interval [CI] 5.5-23.4%) and 0%, respectively. LN was selectively excised (53.8%); upgrade rate in the excision group was 4.8% (95% CI 0.8-22.7%), and with 20 months of median follow-up, no same-site cancers developed in the observation group. Among those not upgraded, the 3-year risk of breast cancer development was 13.1% (95% CI 6.3-26.3%), mostly estrogen receptor-positive (ER +) disease (89.5%). CONCLUSIONS: Upgrade rates for HRLs in patients with PVs in breast cancer predisposition genes appear similar to non-carriers. HRLs may be associated with increased short-term ER+ breast cancer risk in PV carriers, warranting strong consideration of surgical or chemoprevention therapies in this population.

Axillary Staging Is Not Justified in Postmenopausal Clinically Node-Negative Women Based on Nodal Disease Burden.

BACKGROUND: RxPONDER showed no benefit of adjuvant chemotherapy in postmenopausal women with estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer and limited nodal burden (pN1) with a recurrence score ≤ 25, suggesting that axillary staging could be omitted in cN0 patients if significant numbers of such women do not have pN2-3 disease. Here we evaluate the pN2-3 disease rate in a large cohort of postmenopausal women presenting with cN0 breast cancer. PATIENTS AND METHODS: Consecutive postmenopausal patients presenting with T1-2N0 breast cancer who underwent axillary surgery from February 2006 to December 2011 were identified. Clinicopathologic characteristics associated with pN2-3 disease were examined using chi-square or Fisher's exact tests. RESULTS: Of 3363 postmenopausal women with cT1-2N0 breast cancer (median age 58 years, IQR 48-67 years), median tumor size was 1.3 cm (IQR 0.90-1.90cm). Post-axillary staging, 2600 (77.3%) were pN0, 643 (19.1%) were pN1, and 120 (3.6%) were pN2-3. The pN2-3 disease rate did not differ across subtypes (4.4% HER2+, 3.5% HR-/HER2-, 3.5% HR+/HER2-, p = 0.70). In the subset with HR+/HER2- tumors, on multivariable analysis, age < 65 years (odds ratio [OR] 2.38, 95% confidence interval [CI] 1.32-4.49), lymphovascular invasion (OR 5.29, 95% CI 2.72-11.2), multifocal/centric tumors (OR 3.08, 95% CI 1.79-5.32), and tumor size > 2 cm (OR 5.51, 95% CI 3.05-10.4) were significantly associated with pN2-3 nodal burden. Of 506 patients with tumors > 2 cm, 49 (9.7%) had pN2-3 disease; in the subset of 90 patients age < 65 years who had multifocal/centric tumors > 2 cm, 23 (25.6%) had pN2-3 disease. CONCLUSIONS: In postmenopausal women with cN0 disease, pN2-3 nodal burden is uncommon; omitting axillary staging would not miss a significant number of patients who might benefit from adjuvant chemotherapy. Information available preoperatively indicating a higher risk of nodal disease such as younger age and large, multifocal tumors should be considered in the multidisciplinary management of the axilla.

Association of Moderate-Risk Breast Cancer Genes with Contralateral Prophylactic Mastectomy and Bilateral Disease.

BACKGROUND: The impact of ATM, CHEK2, and PALB2, the three most prevalent moderate-risk breast cancer genes, on surgical decision making is not well known. METHODS: Our retrospective study included patients with resectable non-metastatic breast cancer who underwent multigene panel testing between July 2014 and January 2020 with at least one genetic alteration (pathogenic or variant of uncertain significance [VUS] in ATM [n = 49], CHEK [n = 57], or PALB2 [n = 27]). Our objectives were to determine the rate of contralateral prophylactic mastectomy (CPM) and the rate of bilateral breast cancer. Univariable analyses (UVA) and multivariable analyses (MVA) were performed to identify factors associated with CPM and bilateral breast cancer. RESULTS: The rate of CPM was 39% (n = 49/127), with 54% (n = 25/46) of patients with a pathogenic mutation and 30% (n = 24/81) of patients with a VUS choosing CPM. On MVA, premenopausal status (odds ratio [OR] 3.46) and a pathogenic alteration (OR 3.01) were associated with increased use of CPM. Bilateral disease was noted in 16% (n = 22/138). Patients with pathogenic mutations had a 22% (n = 11/51) incidence of bilateral breast cancer, while patients with VUS had a 13% (n = 11/87) incidence, although this was not statistically significant on UVA or MVA. On MVA, premenopausal status was associated with a decreased risk of bilateral disease (OR 0.33, p = 0.022). During follow-up, a breast cancer event occurred in 16% (n = 22/138). CONCLUSIONS: Our study identified a high rate of CPM among those with ATM, CHEK2, and PALB2 alterations, including VUS. Further studies are needed to clarify reasons for CPM among patients with moderate-risk alterations.

Strategies to avoid mastectomy skin-flap necrosis during nipple-sparing mastectomy.

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.

Avoiding Overtreatment of Women ≥70 With Early-Stage Breast Cancer: A Provider-Level Deimplementation Strategy.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Accuracy of the Breast Cancer Surveillance Consortium Model Among Women with LCIS.

PURPOSE: The 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. METHODS: Women 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, age < 35 years or > 74 years, or with 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. RESULTS: 1302 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 10-year BCSC score was significantly lower than the 10-year Tyrer-Cuzick score (10.4 vs 20.8, p < 0.001). The ROC curve scores (AUC) for BCSC at 5 and 10 years were 0.59 (95% CI 0.52-0.66) and 0.58 (95% CI 0.52-0.64), respectively. CONCLUSION: The BCSC model has moderate accuracy in predicting invasive breast cancer risk among women with LCIS with fair discrimination for risk prediction between individuals.

Synchronous and metachronous bilateral breast cancer among women with a history of lobular carcinoma in situ.

PURPOSE: Lobular carcinoma in situ (LCIS) confers increased cancer risk in either breast, but it remains unclear if this population is at increased risk for bilateral breast cancer (BC) development. Here we report bilateral BC incidence among women with a history of LCIS. METHODS: Women with classic-type LCIS diagnosed from 1980 to 2017 who developed unilateral BC (UBC) or bilateral BC were identified. Bilateral BC was categorized as synchronous (bilateral BC diagnosed < 6 months apart; SBBC) or metachronous (bilateral BC diagnosed ≥ 6 months apart; MBBC). Five-year incidence rates of bilateral BC among this population were evaluated. Comparisons were made to identify factors associated with bilateral BC. RESULTS: At 7 years' median follow-up, 249/1651 (15%) women with LCIS developed BC; 34 with bilateral BC (2%). There were no clinicopathologic feature differences between those with UBC and bilateral BC. SBBC occurred in 18 without significant differences versus UBC. Among 211 with UBC and a contralateral breast at risk, 16 developed MBBC at a median follow-up of 3 years. MBBC patients were less likely to receive endocrine therapy and more likely to receive chemotherapy versus UBC. Tumor histology was not associated with MBBC. Estimated 5-year MBBC risk was 6.4%. Index estrogen/progesterone receptor positivity and endocrine therapy were the only factors associated with MBBC risk. CONCLUSION: Bilateral BC occurred in 2% of women with LCIS history at median follow-up of 7 years. Similar to the general BC population, a decrease in MBBC is seen among women with a history of LCIS who develop hormone receptor-positive disease and those who receive endocrine therapy, highlighting the protective effects of this treatment.

Comparison of Outcomes for Classic-Type Lobular Carcinoma In Situ Managed with Surgical Excision After Core Biopsy Versus Observation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Comparison of Outcomes Between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery Versus Mastectomy.

INTRODUCTION: Although outcomes are similar following breast-conserving surgery (BCS) or mastectomy among sporadic breast cancer patients, data are mixed for women with a germline BRCA mutation. We sought to compare outcomes among a modern cohort of BRCA mutation carriers undergoing BCS versus mastectomy. METHODS: Women with a BRCA mutation and an index breast cancer from 2006-2015 were retrospectively identified from institutional databases. Factors, including date of genetic testing, clinicopathologic details, and treatment characteristics, were identified. Subsequent locoregional recurrence (LRR), distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) events were compared between groups. RESULTS: A total of 395 BRCA mutation carriers with 424 cancers were identified. Surgical treatment included BCS for 99 cancers and mastectomy for 325 cancers. Patients choosing mastectomy were more likely to have bilateral breast cancer, be younger/premenopausal, and be aware of their genetic status before surgery, and were less likely to receive radiation therapy (p < 0.001). At 7.9 years median follow-up, LRR, distant recurrence, BCSS, and OS rates did not differ between groups. CBC occurred in 5 versus 0 women treated with unilateral versus bilateral surgery, respectively, resulting is a 10-year estimated CBC risk of 14% among unilateral breast surgery patients (p < 0.001). CONCLUSIONS: With nearly 8 years follow-up, we report no difference in LRR, BCSS, and OS among BRCA mutation carriers who underwent BCS or mastectomy; however, we report a higher incidence of CBC among those undergoing unilateral breast surgery. These data support BCS as an option for BRCA mutation carriers willing to continue high-risk screening.

How Often Do Sentinel Lymph Node Biopsy Results Affect Adjuvant Therapy Decisions Among Postmenopausal Women with Early-Stage HR+/HER2- Breast Cancer in the Post-RxPONDER Era?

BACKGROUND: The RxPONDER trial reported no benefit to chemotherapy among postmenopausal patients with HR+/HER2- tumors, one to three positive nodes, and low recurrence scores, questioning the role of axillary staging in this population. Here, we evaluate the impact of sentinel lymph node biopsy (SLNB) results on adjuvant therapy decisions in postmenopausal women with HR+/HER2- breast cancer. PATIENTS AND METHODS: Postmenopausal women with cT1-2N0, HR+/HER2- breast cancer treated with lumpectomy and SLNB from 2012 to 2018 were identified. Receipt of nodal irradiation, indication for axillary lymph node dissection (ALND) and chemotherapy, and partial breast irradiation (PBI) eligibility were reviewed with pre- and post-SLNB results. RESULTS: A total of 1786 women were identified: median age 62 years, 84% with pT1 tumors, and 16% with pT2-3 tumors. Of those, 85% (n = 1525) remained pN0, 14% (n = 244) were pN1, and 1% (n = 17) were pN2-3. A total of 20 (1%) patients had > 2 positive SLNs, necessitating ALND. Pre-SLNB, 1478 women were considered PBI eligible; post-SLNB, 227 (13%) converted to PBI ineligible. In total, 58 patients with positive nodes received nodal irradiation, representing 3% of the entire cohort and 22% of pN+ patients. Overall, 1401 patients had an Oncotype DX recurrence score available, including 1273 patients with pN0 stage and 128 with pN1, with 173 (14%) and 16 (13%), respectively, having a recurrence score > 25, warranting chemotherapy. CONCLUSIONS: While few cN0 postmenopausal women with HR+/HER2- tumors had nodal pathology that warranted ALND, receipt of nodal irradiation, or indicated need for chemotherapy, in 13%, SLNB would have an impact on consideration for PBI. Among patients eligible for PBI, findings from SLNB may help refine selection among postmenopausal women with this tumor profile.

Axillary Downstaging in Occult Primary Breast Cancer After Neoadjuvant Chemotherapy.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

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

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

Association of Insulin Resistance and Higher Oncotype DX™ Recurrence Score.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 < 0.0001), higher HOMA-IR score (2.4 vs. 1.4, p = 0.004), and more high-grade tumors (30% vs. 16%, p = 0.01). There was a direct positive association with an increasing ODX score and HOMA-IR (p = 0.014). On subset analysis, this relationship was seen in White women (p = 0.005), but not in Black women (p = 0.55). CONCLUSION: In 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.

Insulin resistance contributes to racial disparities in breast cancer prognosis in US women.

BACKGROUND: Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women. METHODS: We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) > 4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC). RESULTS: Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women than in White women (1.9 ± 1.2 vs 1.3 ± 1.4, p = 0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p = 0.004). HOMA-IR was positively associated with NPI score (r = 0.1, p = 0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (ß = 0.04, 95% CI 0.005-0.009, p = 0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p = 0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R >  1: 4.2 ± 0.8 vs IR/IGF-1R = 1: 3.9 ± 0.8 vs IR/IGF-1R < 1: 3.5 ± 1.0, p < 0.0001). CONCLUSIONS: In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.

How Effective is Neoadjuvant Endocrine Therapy (NET) in Downstaging the Axilla and Achieving Breast-Conserving Surgery?

BACKGROUND: 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). METHODS: 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. RESULTS: 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 < 0.05). CONCLUSION: Although nodal pCR is more frequent than breast pCR, NET is more likely to de-escalate breast surgery than axillary surgery. However, with a nodal pCR rate of 11%, NET remains an option for downstaging node-positive patients without clear indications for NAC.

The Tyrer-Cuzick Model Inaccurately Predicts Invasive Breast Cancer Risk in Women With LCIS.

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.

Do Body Mass Index and Breast Density Impact Cancer Risk Among Women with Lobular Carcinoma In Situ?

PURPOSE: Both body mass index (BMI) and breast density impact breast cancer risk in the general population. Whether obesity and density represent additive risk factors in women with lobular carcinoma in situ (LCIS) is unknown. METHODS: Patients diagnosed with LCIS from 1988 to 2017 were identified from a prospectively maintained database. BMI was categorized by World Health Organization classification. Density was captured as the mammographic Breast Imaging Reporting and Data System (BIRADS) value. Other covariates included age at LCIS diagnosis, menopausal status, family history, chemoprevention, and prophylactic mastectomy. Cancer-free probability was estimated using the Kaplan-Meier method, and Cox regression models were used for univariable and multivariable analyses. RESULTS: A total of 1222 women with LCIS were identified. At a median follow-up of 7 years, 179 women developed breast cancer (121 invasive, 58 ductal carcinoma in situ); 5- and 10-year cumulative incidences of breast cancer were 10% and 17%, respectively. In multivariable analysis, increased breast density (BIRADS C/D vs. A/B) was significantly associated with increased hazard of breast cancer (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.52-3.88), whereas BMI was not. On multivariable analysis, chemoprevention use was associated with a significantly decreased hazard of breast cancer (HR 0.49, 95% CI 0.29-0.84). Exploratory analyses did not demonstrate significant interaction between BMI and menopausal status, BMI and breast density, BMI and chemoprevention use, or breast density and chemoprevention. CONCLUSIONS: Breast cancer risk among women with LCIS is impacted by breast density. These results aid in personalizing risk assessment among women with LCIS and highlight the importance of chemoprevention counseling for risk reduction.

Microscopic Extracapsular Extension in Sentinel Lymph Nodes Does Not Mandate Axillary Dissection in Z0011-Eligible Patients.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.