Imaging Characteristics of and Multidisciplinary Management Considerations for Atypical Ductal Hyperplasia and Flat Epithelial Atypia: Review of Current Literature.

High-risk lesions of the breast are frequently encountered in percutaneous biopsy specimens. While benign, these lesions have historically undergone surgical excision due to their potential to be upgraded to malignancy. However, there is emerging evidence that a tailored management approach should be considered to reduce overtreatment of these lesions. Flat epithelial atypia (FEA) and atypical ductal hyperplasia (ADH) are two of the most commonly encountered high-risk lesions. FEA has been shown to have a relatively low rate of progression to malignancy, and some guidelines are now recommending observation over routine excision in select cases. Selective observation may be reasonable in cases where the target lesion is small and completely removed at biopsy and when there are no underlying risk factors, such as a history of breast cancer or genetic mutation or concurrent ADH. ADH has the highest potential upgrade rate to malignancy of all the high-risk lesions. Most society guidelines continue to recommend surgical excision of this lesion. More recently, some literature suggests that ADH lesions that appear completely removed at biopsy, involve limited foci (less than two or three) with no necrosis or significant atypia, manifest as a small group of mammographic calcifications, or demonstrate no enhancement at MRI may be reasonable for observation. Ultimately, management of all high-risk lesions must be based on a multidisciplinary approach that considers all patient, radiologic, clinical, and histopathologic factors. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Is the presence of tumor-infiltrating lymphocytes predictive of outcomes in patients with melanoma?

BACKGROUND: The significance of tumor-infiltrating lymphocytes (TILs) in melanoma is debated. This article presents a multicenter, retrospective study assessing the predictive and prognostic value of TILs. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with known TIL data. TILs were categorized as absent or present, which included nonbrisk (NB), brisk (B), and present but unspecified TIL levels. Clinicopathologic factors were correlated with TILs, sentinel lymph node (SLN) status, and melanoma-specific survival (MSS). RESULTS: Overall, 3203 patients were included. The median thickness was 1.5 mm, and 469 cases had SLN metastases. TILs were present in 2458 cases (76.7%), with NB, B, and unspecified TILs seen in 1691 (68.8%), 691 (28.1%), and 76 (3.1%), respectively. Multivariable analysis showed that the presence of TILs significantly predicted a negative SLN biopsy (P < .05). The median follow-up was 25.2 months. MSS was significantly better for cases with TILs than cases without TILs (P < .001). According to multivariable analysis, age, gender, thickness, mitotic rate, ulceration, lymphovascular invasion, and SLN status were significantly prognostic of MSS (all P values < .05). Although TILs were not prognostic of MSS, when multiple imputation was used and the SLN status was excluded, the presence of TILs was significantly prognostic of improved MSS (hazard ratio, 0.78; 95% confidence interval, 0.64-0.95; P = .0154). CONCLUSIONS: TILs are a favorable marker because their presence significantly predicts a negative SLN, and the absence of TILs may be a prognostic marker of worse survival in patients with a positive SLN but not a negative SLN. TILs may also serve as a prognostic marker of survival when the SLN status is not considered.

Association of breast cancer risk, density, and stiffness: global tissue stiffness on breast MR elastography (MRE).

PURPOSE: Quantify in vivo biomechanical tissue properties in various breast densities and in average risk and high-risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association between breast biomechanical properties and cancer risk based on patient demographics and clinical data. METHODS: Patients with average risk or high-risk of breast cancer underwent 3.0 T breast MR imaging and elastography. Breast parenchymal enhancement (BPE), density (from most recent mammogram), stiffness, elasticity, and viscosity were recorded. Within each breast density group (non-dense versus dense), stiffness, elasticity, and viscosity were compared across risk groups (average versus high). Separately for stiffness, elasticity, and viscosity, a multivariable logistic regression model was used to evaluate whether the MRE parameter predicted risk status after controlling for clinical factors. RESULTS: 50 average risk and 86 high-risk patients were included. Risk groups were similar in age, density, and menopausal status. Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high-risk patients (N = 55) compared to average risk patients (N = 34; all p < 0.001). Stiffness remained a significant predictor of risk status (OR = 4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, BPE, age, and menopausal status. Similar results were seen for elasticity and viscosity. CONCLUSION: A structurally based, quantitative biomarker of tissue stiffness obtained from MRE is associated with differences in breast cancer risk in dense breasts. Tissue stiffness could provide a novel prognostic marker to help identify high-risk women with dense breasts who would benefit from increased surveillance and/or risk reduction measures.

Accuracy of Posttreatment Imaging for Evaluation of Residual in Breast Disease After Neoadjuvant Endocrine Therapy.

BACKGROUND: Neoadjuvant endocrine therapy (NET) can help downstage certain breast cancers prior to surgical resection. This study measured the accuracy of conventional mammography (MMG), ultrasound (US), magnetic resonance imaging (MRI), and contrast-enhanced mammography (CEM) for assessing breast tumor size in response to NET. PATIENTS AND METHODS: Patients who underwent surgery after NET from 2013 to 2021 were identified. The maximal dimension of residual tumor on imaging was compared with the maximal dimension on final pathology. Lin's concordance correlation coefficient (rc) and Spearman's rank correlation coefficient (r) were used to assess agreement. RESULTS: In total, 119 patients with invasive breast cancer underwent NET, posttreatment imaging, and surgery. Tumor size reported on posttreatment CEM correlated with size on final pathology to within 1 cm in n = 42 (58%) of patients, equivalent to the accuracy of MRI (n = 35, 58%). Size was accurately predicted by US in 54% and in 48% of MMG. Posttreatment imaging tumor size was moderately correlated with final tumor size on pathology CEM (r = 0.49; rc = 0.38), MRI (r = 0.52; rc = 0.45), and US (r = 0.41; rc = 0.28). MMG was weakly correlated (r = 0.21; rc = 0.16). Similar findings were shown in subgroup analysis; in those who received all four post-NET imaging, CEM and MRI again performed comparably, with r = 0.36 and 0.41, respectively, US (r = 0.43) and MMG (r = 0.28). CONCLUSIONS: Compared with mammography and US, CEM and MRI had higher accuracy in estimating final tumor size for breast cancers treated with NET. Contrast-enhanced imaging is a helpful adjunct when response to preoperative therapy will impact clinical management.

Postoperative Hematomas in the Era of Outpatient Mastectomy: Is Ketorolac Really to Blame?

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols following mastectomy with or without implant-based breast reconstruction (IBBR) include ketorolac for multimodal perioperative analgesia. There are concerns that ketorolac could be associated with increased risk of postoperative hematoma formation. METHODS: Retrospective review of patients undergoing mastectomy with or without IBBR between January 2013 and December 2019 at a single institution. Patients received 15 mg, 30 mg, or no ketorolac depending on ERAS protocol adherence, patient characteristics, and surgeon preference. Clinically significant hematoma was defined as requiring surgical intervention on day of surgery or postoperative day 1. Patients were compared by demographics, surgical characteristics, ketorolac dose, and hematoma prevalence. Univariable and multivariable logistic regression evaluated hematoma formation odds. RESULTS: Eight hundred patients met inclusion criteria: 477 received ketorolac. Those who received ketorolac were younger, had lower ASA scores, were more likely to have bilateral procedures and undergo concomitant IBBR, had longer operative times, were less likely to take antiplatelet or anticoagulation medications, had higher PACU pain scores, and had higher incidence of hematomas requiring surgical intervention. Of the cohort, 4.4% had clinically significant hematomas. The 15 mg and 30 mg ketorolac groups had similar prevalence (6.0% vs 5.8%, p = 0.95). On univariable regression, there were increased odds of hematoma formation in patients who were younger, had bilateral procedures, had longer OR times, and who received ketorolac. On multivariable regression, none of the prior variables remained significant. CONCLUSION: After accounting for associations with longer operative times, concomitant IBBR, and bilateral procedures, ketorolac administration did not remain an independent risk factor for hematoma formation.

Merkel cell carcinoma of unknown primary: Clinical presentation and outcomes.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy that usually occurs in the head/neck or extremities. However, there are reports of MCC developing in the lymph nodes or parotid gland without evidence of a primary cutaneous lesion. METHODS: We reviewed 415 patients with biopsy-proven MCC. Patients with MCC of unknown primary (n = 37, 9%, MCCUP) made up the study cohort. The primary endpoints of the study were rate of recurrence, disease-free survival, and overall survival. RESULTS: Patients with MCCUP presented with tumors in lymph nodes (n = 34) or parotid gland (n = 3). Nodal disease was most commonly detected in the inguinal/external iliac (n = 15) or axillary (n = 14) regions. The mean age at diagnosis was 70 years and 24% were female. Patients presented with distant metastases in 24.3% of cases. Patients with stage IIIA disease treated with regional lymph node dissection (RLND) had a lower risk of disease recurrence (hazard ratio 0.26, p = 0.046). Recurrence-free survival was 59.3% at 5 years. Disease-specific survival was 63.3% at 5 years. CONCLUSION: Patients with MCCUP have a high risk of recurrence and mortality. The optimal treatment for MCCUP has yet to be elucidated, although therapeutic RLND appears beneficial for these patients.

Chest wall resection for breast cancer: 21st century Mayo clinic experience.

BACKGROUND: We hypothesized full-thickness chest wall resection (FTCWR) with advanced surgical techniques and modern systemic therapy is safe, provides local control, and good overall survival. METHODS: Retrospective review of FTCWR (including rib or part of sternum) for breast cancer between 2000 and 2020. Primary endpoints included 90-day morbidities and all-cause mortality. Secondary endpoints were loco-regional and distant recurrence, DFS and overall survival (OS). RESULTS: A total of 35 patients met the criteria. 34 FTCWR were for recurrence and the median time to chest wall recurrence was 6 years. Tumor subtype was triple-negative in 51% and the remainder HR+ Her2-. 58% were palliative resections. FTCWR included rib(s) in 89% and portion of sternum in 57%; 94% required reconstruction and 80% were R0 resections. There were no 90-day mortalities. Overall morbidity was 10/35(28%). 17(49%) patients received neoadjuvant systemic therapy for their recurrence and three received neoadjuvant radiation. Adjuvant treatment included chemotherapy (8), endocrine therapy (3), and both (8). Ten patients (28%) received adjuvant radiation. The Median follow-up was 31 months and there were 6 (17%) loco-regional and 7 (20%) distant recurrences. OS was 86% and 67% at 1 and 3 years, respectively. CONCLUSION: FTCWR was associated with low morbidity, mortality, recurrence rates, and good OS. Selective FTCWR is safe and has acceptable short-term survival rates.

Lymph node positivity and association with long-term survival for different histologies of appendiceal cancer.

BACKGROUND: Appendiceal cancers represent a diverse group of malignancies with varying biological behavior. The significance of lymph node metastases in relation to long-term survival and chemotherapy response is poorly defined. METHODS: The National Cancer Database was queried to find patients diagnosed with appendiceal cancer from 1998 to 2012. Kaplan-Meier curves and multivariable Cox regression analyses were used to study the association between lymph node status and overall survival. Stage IV patients were excluded. RESULTS: The rate of nodal positivity of the 9841 patients with known node status was: signet ring 47.4%, carcinoid 42.3%, nonmucinous adenocarcinoma 28.8%, goblet cell 21.9%, and mucinous adenocarcinoma 20.4%. Node-positive patients had worse long-term survival for all subtypes with the exception of carcinoid tumors (p < 0.001). The strongest association was for signet cell and goblet cell. Adjuvant chemotherapy in node-positive patients improved survival for mucinous, nonmucinous, and signet ring cell histology (p < 0.01), but not for goblet cell. CONCLUSIONS: Nodal involvement in patients with appendiceal cancer varies in incidence, association with adverse survival, and response to systemic therapy. Individualized treatment algorithms for the management of the subtypes of appendiceal cancer are needed.

Unplanned implant removal in locally advanced breast cancer.

Study conducted to determine frequency and timing of unplanned breast implant removal after mastectomy, reconstruction, and postmastectomy radiation (PMRT). From 2010-2017, 52 patients underwent mastectomy, reconstruction, and PMRT. With median follow-up of 3.1 years, 23 patients (44%) experienced implant removal. Implant removal occurred in 9 (17%) patients before starting PMRT and 14 (27%) patients after starting PMRT. Implant removal rates were similar for hypofractionated PMRT compared with standard fractionation and for proton compared with photon PMRT. Implant removal is common for women undergoing mastectomy and reconstruction followed by PMRT. The risk is clinically significant even before starting radiation.

Same-day Discharge Is Safe and Effective After Implant-Based Breast Reconstruction.

BACKGROUND: Same-day discharge after mastectomy is a recently described treatment approach. Limited data exist investigating whether same-day discharge can be successfully implemented in patients undergoing mastectomy with immediate implant-based breast reconstruction (IBR). METHODS: Patients having mastectomy with IBR from 2013 to 2019 were reviewed. Enhanced recovery with same-day discharge was implemented in 2017. Patient characteristics, oncologic treatments, surgical techniques, and 90-day postoperative complications and reoperations were analyzed comparing enhanced recovery patients with historical controls. RESULTS: A total of 363 patients underwent nipple-sparing (214, 59%) or skin-sparing (149, 41%) mastectomy with 1-stage (270, 74%) or tissue expander (93, 26%) IBR. Enhanced recovery was used for 151 patients, with 79 of these patients (52%) discharged same-day. Overall, enhanced recovery patients experienced a significantly lower rate of 90-day complications (21% vs 41%, P < 0.001), including hematoma (3% vs 11%, P = 0.002), mastectomy flap necrosis (7% vs 15%, P = 0.02), seroma (1% vs 9%, P < 0.001), and wound breakdown (3% vs 9%, P = 0.05). Postoperative complication rates did not significantly differ among enhanced recovery patients discharged same day. Postoperative admissions significantly decreased after enhanced recovery implementation (100% to 48%, P < 0.001), and admitted enhanced recovery patients experienced a lower length of stay (1.2 vs 1.8, P < 0.001). Enhanced recovery patients experienced a lower incidence of ≥1 unplanned reoperation (22% vs 33%, P = 0.01); overall average unplanned and total reoperations did not significantly differ between groups. CONCLUSIONS: In conjunction with enhanced recovery practices, same-day discharge after mastectomy with IBR is a safe and feasible treatment approach.

Does Prior Breast Augmentation Affect Outcomes After Mastectomy With Reconstruction? An Analysis of Postoperative Complications and Reoperations.

BACKGROUND: The purpose of this study is to evaluate how prior breast augmentation impacts rates of complications and risk for reoperation after mastectomy with concurrent breast reconstruction. METHODS: Patients undergoing nipple-sparing, skin-sparing, or simple mastectomy with implant-based reconstruction from 2008 to 2018 were identified in a prospective database. Postoperative complications and reoperations were then analyzed comparing patients with prior augmentation to patients without history of previous breast surgery. RESULTS: A total of 468 patients were identified with a median follow-up of 4 years. Of these, 72 had prior augmentation mammoplasty. These patients underwent nipple-sparing (52, 72%), skin-sparing (15, 21%), or simple (5, 7%) mastectomy with immediate direct-to-implant (46, 61%) or tissue expander (26, 35%) reconstruction. On univariate analysis, this cohort had a lower body mass index (23.3 vs 25.3, P = 0.003), a higher rate of nipple-sparing mastectomy (72% vs 54%, P = 0.01), and a higher prevalence of stage I disease (44% vs 33%, P = 0.04). Differences in age, comorbidities, reconstructive techniques, tumor size, and neoadjuvant/adjuvant therapies were not significant. Overall complication rate between patients with or without prior augmentation did not significantly differ (51% vs 50%, P = 0.83); no significant differences in rates of surgical site infection, hematoma, mastectomy skin flap/wound necrosis, nipple complications, implant loss, or capsular contracture were found. Analysis of reoperations between patients with and without prior augmentation revealed no significant differences in average number of subsequent planned, unplanned, or total reoperations. On multivariate analysis, prior breast augmentation was found to be associated with significantly increased risk for undergoing ≥1 unplanned reoperation (odds ratio, 2.28; 95% confidence interval, 1.28-4.05, P = 0.005). CONCLUSIONS: Prior augmentation mammoplasty does not significantly affect rates of postoperative complications after mastectomy with concurrent reconstruction. Although prior augmentation does not affect number of subsequent reoperations on average, it does increase the risk of experiencing 1 or more unplanned reoperation after mastectomy with reconstruction.

Impact of adjuvant trastuzumab on locoregional failure rates in a randomized clinical trial: North Central Cancer Treatment Group N9831 (alliance) study.

BACKGROUND: The goal of this study was to assess the impact of trastuzumab on locoregional failure. METHODS: The analysis included 2763 patients with HER2-positive (HER2+) breast cancer who were randomly assigned to adjuvant doxorubicin (A), cyclophosphamide (C), paclitaxel (T) and trastuzumab (H) (arm A, AC→T [n = 922]; arm B, AC→T→H [n = 988]; arm C, AC→T+H→H [n = 853]). Radiotherapy was given after AC→T concurrently with H. Radiotherapy was given after lumpectomy (L) or after mastectomy (M) with ≥4 positive lymph nodes but was optional for 1 to 3 positive lymph nodes. Locoregional failures at 10 years (LFR10) as first events were compared using competing risk analysis. RESULTS: The median follow-up was 13.0 years. The first site of failure was local-only in 96 cases, locoregional in 16 cases, regional in 32 cases, and not specified in 2 cases; LFR10 was 4.8% (95% CI 4.1%-5.7%). LFR10 was 5.5% (95% CI 4.3%-7.2%), 4.9% (95% CI 3.7%-6.4%), and 2.8% (95% CI 1.9%-4.1%) in arms A, B, and C (B vs A: hazard ratio [HR] 0.91, P = .62; C vs A: HR 0.72, P = .12). For estrogen receptor-positive patients, LFR10 was 3.7% (95% CI 2.8%-4.8%) and for estrogen receptor-negative patients, it was 6.1% (95% CI 5.0%-7.4%; HR 0.61, P = .004). Local treatment included L+RT (n = 1044 [38%]), M+RT (n = 1025 [37%]), and M (n = 694 [25%]). LFR10 was 6.% (95% CI 5.0%-7.8%), 3.0% (95% CI 2.1%-4.3%), and 5.5% (95% CI 4.0%-7.4%) for L+RT, M+RT, and M, respectively (M+RT vs L+RT: HR 0.43, P < .001; M vs L+RT: HR 0.88, P = .57). For 1 to 3 positive lymph nodes, LFR10 was 6.5% (95% CI 4.8%-8.9%), 4.1% (95% CI 2.4%-7.0%), and 4.3% (95% CI 2.9%-6.5%) in L+RT, M+RT, and M, respectively (M vs L+RT: HR 0.68, P = .14; M vs M+RT: HR 1.2, P = .6). CONCLUSION: Low 10-year LFRs were seen regardless of trastuzumab use. Differences in local therapy in patients with 1 to 3 positive lymph nodes did not appear to improve local control. Local therapy studies for HER2+ and other tumor characteristics are important as the role of local therapies continues to evolve.

Implementation of an Enhanced Recovery After Surgery (ERAS) Program is Associated with Improved Outcomes in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been associated with increased postoperative complications and a prolonged length of stay (LOS). We report on our experience following implementation of an Enhanced Recovery After Surgery (ERAS) program for CRS and HIPEC. METHODS: Patients were divided into pre- and post-ERAS groups. Modifications in the ERAS group included routine use of transversus abdominis plane blocks, intra- and postoperative fluid restriction, and minimizing the use of narcotics, drains, and nasogastric tubes. RESULTS: Of a total of 130 procedures, 49 (38%) were in the pre-ERAS group and 81 (62%) were in the ERAS group. Mean LOS was reduced from 10.3 ± 8.9 days to 6.9 ± 5.0 days (p = 0.007) and the rate of grade III/IV complications was reduced from 24 to 15% (p = 0.243) following ERAS implementation. The ERAS group received less intravenous fluid during hospitalization (19.2 ± 18.7 L vs. 32.8 ± 32.5 L, p = 0.003) and used less opioids than the pre-ERAS group (median of 159.7 mg of oral morphine equivalents vs. 272.6 mg). There were no significant changes in the rates of 30-day readmission or acute kidney injury between the two groups (p = non-significant). On multivariable analyses, ERAS was significantly associated with a reduction in LOS (- 2.89 days, 95% CI - 4.84 to - 0.94) and complication rates (odds ratio 0.22, 95% CI 0.08-0.57). CONCLUSIONS: Implementation of an ERAS program for CRS and HIPEC is associated with a reduction in overall intravenous fluids, postoperative narcotic use, complication rates, and LOS.

Clinical significance of SLN benign capsular nevi in patients with melanoma.

BACKGROUND: Benign capsular nevi (BCN) are not infrequent in sentinel lymph nodes (SLN) of patients with melanoma. Their prognostic significance is unknown and the literature is limited. This study evaluated the clinical significance of incidentally found BCN in these patients. METHODS: A multi-institutional retrospective review of patients undergoing SLN biopsy for cutaneous melanoma between 2000 and 2016. Patients were divided into the following groups: (a) negative SLN and no BCN, (b) negative SLN and presence of BCN, (c) positive SLN seen only on immunohistochemistry (IHC), and (d) positive SLN via hematoxylin and eosin (H&E). Outcomes measured were overall survival and any recurrence. RESULTS: A total of 1253 patients were identified (group 1 = 978, group 2 = 56, group 3 = 32, and group 4 = 187). Fifty-seven percent were male and the mean age was 59.3 years. BCN was identified in 77 patients (6.2%), of which the majority was in the node-negative group (72%). Multivariable analysis showed that BCN was associated with lower recurrence rates, though not statistically significant (hazard ratio [HR] = 0.5; P = .06). IHC- and H&E-positive SLNs were associated with a higher risk of recurrence (HR = 2.4; P = .02 and 2.0, P < .0001, respectively). CONCLUSION: Patients with BCN and negative SLN had lower recurrence rates than patients with negative SLN and no BCN. Our data suggest a possible protective effect against recurrence.

Gauging the efficacy of neoadjuvant endocrine therapy in breast cancer patients with known axillary disease.

BACKGROUND AND OBJECTIVES: Neoadjuvant endocrine therapy (NET) for ER+ breast cancer can downstage primary tumors. We evaluated NET efficacy in node-positive patients. METHODS: Node-positive patients undergoing NET for ER+ breast cancer from 2012 to 2019 were reviewed. Primary endpoints included rates of axillary lymphadenectomy (ALND), pathologic complete response (pCR), and final nodal staging. RESULTS: Thirty-nine patients were included. Before NET, all were clinically node-positive (cN1 = 36, 94%; cN2 = 2, 5%; cN3 = 1, 3%; Stage II = 23, 59%, Stage III = 16, 41%). After NET, nine (23%) had clinically persistent axillary disease necessitating ALND. The remaining 30 (77%) underwent sentinel lymph node biopsy (SLNB). Of these, 25 (83%) were SLNB+ on frozen section, undergoing immediate ALND. Five patients were negative on frozen section: one had a confirmed axillary pCR, and four had residual nodal disease on permanent pathology. One underwent delayed ALND, and for the remaining three patients, decision was made to forgo ALND. Final overall axillary staging was: N0 (pCR) = 1, 3%, pN1mic = 1, 3%, pN1 = 20, 51%, pN2 = 12, 30%, pN3 = 5, 13%; Stage II = 16, 41%, Stage III = 23, 59%. CONCLUSIONS: While NET is reported to downstage primary tumors, downstaging of the axilla was unsuccessful in the majority of patients.

Depomedroxyprogesterone acetate therapy for hot flashes in survivors of breast cancer: no unfavorable impact on recurrence and survival.

PURPOSE: Survivors of estrogen receptor-expressing breast cancer generally do not receive estrogen-based therapy for menopausal symptoms due to concern for provoking recurrence of disease. Single-dose depomedroxyprogesterone acetate has been shown to be among the most effective non-estrogen strategies for treatment of menopausal hot flashes, but long-term evidence for safety in survivors is lacking. METHODS: We conducted an institutional review board approved, retrospective, case-control cohort study at a tertiary, academic referral center. Patients with estrogen receptor-expressing early-stage operable breast cancer who received depomedroxyprogesterone acetate for hot flashes between January 2005 and December 2012 were identified. We confirmed 75 patients who met strict inclusion criteria who were matched 1:1 with controls for age, stage of disease, HER2 status, and year of diagnosis. Overall survival, loco-regional recurrence-free survival, and progression-free survival assessments for cases were compared with controls. RESULTS: Median follow-up duration was 68.4 months in cases and 57.6 months in controls. Estimated local-regional recurrence-free survival at 10 years was 97% (95% CI, 92-100%) in cases and 98% (95% CI, 95-100%) in controls. Estimated progression-free survival at 10 years was 89% (95% CI, 80-100%) in cases and 83% (95% CI, 73-95) in controls. The majority (75%) of case patients experienced satisfactory relief of hot flashes from depomedroxyprogesterone injection. DISCUSSION: In this retrospective case-control study, we were unable to identify a detrimental effect of depomedroxyprogesterone acetate therapy for hot flashes in survivors of estrogen receptor-expressing breast cancer. Depomedroxyprogesterone acetate may be acceptable for management of hot flashes in this population.

Microsatellitosis in Patients with Melanoma.

BACKGROUND: Microsatellitosis (mS) in melanoma has been considered a marker of unfavorable tumor biology, leading to the current American Joint Committee on Cancer staging of IIIB/C/D disease, despite few investigative studies of this entity limited by the small sample sizes and incomplete nodal microstaging. We sought to better characterize outcomes and prognostic factors in a multi-institutional cohort of patients with mS and nodal microstaging. METHODS: The Sentinel Lymph Node Working Group cohort included 414 mS patients who underwent sentinel lymph node (SLN) biopsy. Cox regression analysis was used to evaluate the prognostic significance of established clinicopathologic characteristics. Melanoma-specific survival (MSS) of patients with mS was compared with 3002 similarly staged patients from the Surveillance, Epidemiology, and End Results (SEER) Program registry. RESULTS: The median age of the mS cohort was 64.9 years; 39.6% were female. Median thickness was 3 mm, 40.6% of cases were ulcerated, and the SLN positivity rate was 46.7%. Increasing thickness, male sex, and SLN positivity were significantly associated with poorer MSS. Stage IIIB/C/D 5-year MSS rates were 86.3% (95% confidence interval [CI] 79.4-93.3%), 54.1% (95% CI 45.4-59.7%), and 44.2% (95% CI 25.4-63.0%), respectively. MSS survival for the stage IIIB mS cohort was significantly better than a similarly staged SEER cohort (5-year MSS of 70.1%, 95% CI 66.0-74.2%), while no significant difference was observed for the stage IIIC or D cohorts. CONCLUSIONS: SLN metastases are common and are a significant prognostic factor in patients with mS. Survival in stage IIIB patients with mS was considerably more favorable than their stage would otherwise suggest, which has important implications for decisions regarding adjuvant therapy for patients with mS.

Relationship between age and likelihood of lymph node metastases in patients with intermediate thickness melanoma (1.01-4.00 mm): A National Cancer Database study.

BACKGROUND: There is large variability in the risk of sentinel lymph node (SLN) positivity among patients with intermediate thickness melanoma (ITM), with a subgroup of patients exhibiting a low risk of nodal disease. OBJECTIVE: To identify a group of patients with ITM for whom the risk of nodal disease is low. METHODS: A retrospective cohort of patients with ITM who underwent wide excision and nodal evaluation from 2010 to 2013 was identified by using the National Cancer Database and analyzed for the presence of nodal disease. Classification and regression tree analysis identified the most important factors used in a model to identify groups at low risk of SLN positivity. RESULTS: Of 23,440 patients, 14.7% were found to have nodal metastasis. On classification and regression tree analysis, patients older than 55 years without lymphovascular invasion and with a lesion thickness less than 1.7 mm had an SLN positivity rate of 4.9%. A model using age and thickness in nonulcerated patients identified a low-risk subgroup with a corresponding SLN positivity rate of 4.7%. LIMITATIONS: This was a retrospective study, and the model developed requires prospective validation. CONCLUSIONS: Patient age is an important factor in estimating risk of SLN in patients with ITM and may help identify patients without ulceration who may be safely spared an SLN biopsy.

The association of genomic lesions and PD-1/PD-L1 expression in resected triple-negative breast cancers.

BACKGROUND: Elevated PD-L1 expression on tumor cells, a context associated with an adaptive immune response, has been linked to the total burden of copy number variants (CNVs) in aneuploid tumors, to microsatellite instability (MSI), and to specific genomic driver lesions, including loss of PTEN, MYC amplification, and activating mutations in driver oncogenes such as KRAS and PIK3CA. Triple-negative breast cancers (TNBCs) typically have high levels of CNVs and diverse driver lesions in their genomes. Thus, there is significant interest in exploiting genomic data to develop predictive immunotherapy biomarkers for patients with TNBC. METHODS: Whole tissue samples from 55 resected TNBCs were screened by immunohistochemistry (IHC) for PD-1 and PD-L1 by using validated antibodies and established scoring methods for staining of tumor and non-tumor cells. In parallel, we interrogated biopsies from each resection with DNA content flow cytometry and sorted the nuclei of diploid, tetraploid, and aneuploid cell populations. CNVs were mapped with CNV oligonucleotide arrays by using purified (>95%) tumor populations. We generated whole exome data for 12 sorted tumor samples to increase the resolution within loci of interest and to incorporate somatic mutations into our genomic signatures. RESULTS AND CONCLUSIONS: PD-L1 staining was detected on tumor cells in 29 out of 54 (54%) evaluable cases and was associated with increased overall survival (P = 0.0024). High levels of PD-1 and PD-L1 (IHC ≥4) were present in 11 out of 54 (20%) and 20 out of 54 (37%) cases with staining of PD-L1 primarily on tumor cells for 17 out of 20 (85%) cases. The latter included tumors with both high (>50) and low (<20) numbers of CNVs. Notably, homozygous deletion of PTEN (n = 6) or activating mutation in PIK3CA (n = 1) was not associated with increased expression of either immune checkpoint activator in TNBC. In contrast, two treatment-naïve cases with EGFR driver amplicons had high PD-L1 tumor staining. High mutational load and predicted neoepitopes were observed in MSI+ and high CNV burden TNBCs but were not associated with high PD-L1 expression on tumor cells. Our results challenge current models of genomic-based immunotherapy signatures yet suggest that discrete genomic lesions may complement existing biomarkers to advance immune checkpoint therapies for patients with TNBC.

Intraoperative Margin Management in Breast-Conserving Surgery: A Systematic Review of the Literature.

BACKGROUND: Breast surgeons have a wide variety of intraoperative techniques available to help achieve low rates for positive margins of excision, with variable levels of evidence. METHODS: A systematic review of the medical literature from 1995 to July 2016 was conducted, with 434 abstracts identified and evaluated. The analysis included 106 papers focused on intraoperative management of breast cancer margins and contained actionable data. RESULTS: Ultrasound-guided lumpectomy for palpable tumors, as an alternative to palpation guidance, can lower positive margin rates, but the effect when used as an alternative to wire localization (WL) for nonpalpable tumors is less certain. Localization techniques such as radioactive seed localization and radioguided occult lesion localization were found potentially to lower positive margin rates as alternatives to WL depending on baseline positive margin rates. Intraoperative pathologic methods including gross histology, frozen section analysis, and imprint cytology all have the potential to lower the rates of positive margins. Cavity-shave margins and the Marginprobe device both lower rates of positive margins, with some potential for negative cosmetic effects. Specimen radiography and multiple miscellaneous techniques did not affect positive margin rates or provided too little evidence for formation of a conclusion. CONCLUSIONS: A systematic review of the literature showed evidence that several intraoperative techniques and actions can lower the rates of positive margins. These results are presented together with graded recommendations.