Dose de-intensified 3-day photon, proton, or brachytherapy: a nonrandomized controlled partial breast irradiation trial.

BACKGROUND: The optimal approach for partial breast irradiation (PBI) is unknown. We investigated a novel de-intensified 3-fraction PBI regimen for photons, protons, and brachytherapy. METHODS: A multicenter nonrandomized controlled trial with primary outcome of adverse cosmesis at 3 years versus pre-PBI. Eligibility criteria were ≥ age 50 years treated with breast-conserving surgery for node-negative estrogen receptor positive (ER+) invasive breast cancer or any ductal carcinoma in-situ (DCIS) measuring ≤ 2.5 cm. Photon and proton PBI were prescribed 21.9 Gy (RBE) and brachytherapy 21 Gy in 3 fractions. Radiotherapy technique and use of adjuvant endocrine therapy was selected at physician and patient discretion. RESULTS: Between June 17, 2015 and July 13, 2017, 161 eligible patients were treated with photons (56), protons (49), or brachytherapy (56). Median patient age was 66.8 years. 126 (78.3%) had invasive breast cancer (all ER+) and 35 (21.7%) had DCIS (88.6% ER+). 54.0% of patients with invasive breast cancer and 25.8% of patients with ER+ DCIS initiated and adhered to prescribed endocrine therapy. The proportion of patients with adverse cosmesis (by trained nurse assessment) was 14.5% at baseline, 2.3% at 3 years (difference -12.2%, 95% CI (-100%, -6.4%)). Adverse cosmesis at last-follow-up, with median follow-up 5 years, was 5.7% by nurse assessment, 5.6% by panel assessment of digital photographs, and 5.2% by patient self-report. There were no observed clinically meaningful changes in other patient reported outcomes, and just two grade 2 or higher adverse events, both grade 2, in the brachytherapy cohort. 5-year local recurrence-free and progression-free survival were 98.0% and 95.5%, respectively. There were no local recurrences amongst 60 patients with invasive breast cancer and Ki67 ≤ 13.25%. CONCLUSIONS: De-intensified 3-day PBI provided favorable disease control, tolerability, and cosmetic outcomes, meeting the pre-specified criteria for acceptability. This approach is an attractive option for small node-negative ER+ BC and DCIS patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02453737.

Germline genetic mutations in a multi-center cohort of 248 phyllodes tumors.

PURPOSE: Germline genetic mutations in women with phyllodes tumors (PT) are understudied, although some describe associations of PT with various mutations. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in women with PT. METHODS: A 6-site multi-center study of women with a PT was initiated, then expanded nationally through an online "Phyllodes Support Group." All women underwent 84-gene panel testing. We defined eligibility for testing based on select NCCN (National Comprehensive Cancer Network) criteria (v1.2022). Logistic regression was used to estimate the association of covariates with the likelihood of a P/LP variant. RESULTS: 274 women were enrolled: 164 (59.9%) through multi-center recruitment and 110 (40.1%) via online recruitment. 248 women completed testing; overall 14.1% (N = 35) had a P/LP variant, and over half (N = 19) of these individuals had a mutation in genes associated with autosomal dominant (AD) cancer conditions. The most common AD genes with a P/LP variant included CHEK2, ATM, and RAD51D. A quarter of participants (23.8%) met NCCN criteria for testing, but we found no difference in prevalence of a P/LP variant based on eligibility (p = 0.54). After adjustment, the presence of P/LP variants was not associated with age, NCCN testing eligibility, or PT type (all p > 0.05). CONCLUSION: Our study demonstrates that 7.7% of women with PT harbor germline P/LP variants in genes associated with AD cancer conditions. Early identification of these variants has implications for screening, risk reduction, and/or treatment. National guidelines for women with PT do not currently address germline genetic testing, which could be considered.

Clipped Axillary Node as a Potential Surrogate for Overall Axillary Nodal Status in Inflammatory Breast Cancer Patients after Neoadjuvant Chemotherapy.

BACKGROUND: Axillary lymph node dissection is the current standard for management of the axilla in inflammatory breast cancer (IBC). The present study aims to determine whether the initially positive node identified by clip placement accurately represents the overall nodal status of axilla after neoadjuvant chemotherapy (NAC) in IBC. PATIENTS AND METHODS: A retrospective study was conducted on patients with IBC who underwent operation (2014-2023). For patients with IBC who had clip placement in a positive axillary node at diagnosis, operative notes, specimen radiographs, and pathology reports were reviewed to confirm final pathologic status of clipped nodes. RESULTS: In total, 92 patients with IBC (90 cN+) were identified (median age 54 years, 78% invasive ductal, 10% invasive lobular, and 12% mixed); 81 (90%) were biopsy-proven cN+, with a clip placed in the positive node for 62/81 (77%). All patients were treated with NAC and axillary surgery with median 19 (range 4-49) nodes removed. Among 28 (out of 56) patients with retrieved clipped nodes that were pathologically negative (ypN0), only 1 had an additional positive node with micrometastasis for a false negative rate of 4% (95% CI 1-19%). Conversely, 3/3 patients with isolated tumor cells (ITCs) only in the clipped node had additional axillary disease (ITCs in 1, macrometastasis in 2), and 20/23 (87%) of patients with pathologically positive clipped node (micrometastasis or greater) had additional positive nodes [19/20 (95%) with macrometastasis]. CONCLUSIONS: The clipped biopsy-positive axillary node in IBC accurately represented the post-NAC overall axillary nodal status. ITCs post-NAC should be considered positive as an indicator of additional nodes with metastasis.

Advances from targeted therapy for non-metastatic HER2-positive inflammatory breast cancer.

Among inflammatory breast cancer (IBC) patients, over one-third have HER2-overexpressing (HER2+) tumors. Pathologic complete response (pCR) rates to neoadjuvant targeted and chemotherapy for patients with HER2+ non-metastatic IBC now apporach 60% and favorable long-term survival rates are being reported for those with a pCR. Immune mechanisms contributing to this phenomenon include antibody-mediated immune activation and induction of memory T-cell reponses which may explain the sustained antitumor response seen after discontinuation of targeted therapies.

Lymphedema Rates Following Axillary Lymph Node Dissection With and Without Immediate Lymphatic Reconstruction: A Prospective Trial.

BACKGROUND: Immediate lymphatic reconstruction (ILR) has been proposed to decrease lymphedema rates. The primary aim of our study was to determine whether ILR decreased the incidence of lymphedema in patients undergoing axillary lymph node dissection (ALND). METHODS: We conducted a two-site pragmatic study of ALND with or without ILR, employing surgeon-level cohort assignment, based on breast surgeons' preferred standard practice. Lymphedema was assessed by limb volume measurements, patient self-reporting, provider documentation, and International Classification of Diseases, Tenth Revision (ICD-10) codes. RESULTS: Overall, 230 patients with breast cancer were enrolled; on an intention-to-treat basis, 99 underwent ALND and 131 underwent ALND with ILR. Of the 131 patients preoperatively planned for ILR, 115 (87.8%) underwent ILR; 72 (62.6%) were performed by one breast surgical oncologist and 43 (37.4%) by fellowship-trained microvascular plastic surgeons. ILR was associated with an increased risk of lymphedema when defined as ≥10% limb volume change on univariable analysis, but not on multivariable analysis, after propensity score adjustment. We did not find a statistically significant difference in limb volume measurements between the two cohorts when including subclinical lymphedema (≥5% inter-limb volume change), nor did we see a difference in grade between the two cohorts on an intent-to-treat or treatment received basis. For all patients, considering ascertainment strategies of patient self-reporting, provider documentation, and ICD-10 codes, as a single binary outcome measure, there was no significant difference in lymphedema rates between those undergoing ILR or not. CONCLUSION: We found no significant difference in lymphedema rates between patients undergoing ALND with or without ILR.

ASO Author Reflections: Time to Explore Minimally Invasive Axillary Nodal Staging After Neo-Adjuvant Chemotherapy in Inflammatory Breast Cancer.

In inflammatory breast cancer (IBC), obstructed lymphatics present a barrier to sentinel node biopsy. In theory this challenge could be overcome by clipping the clinically positive node at presentation and surgically retrieving it after neoadjuvant chemotherapy (NAC). If the clipped node accurately reflects the axillary status, then deescalation of axillary nodal dissection could be a possibility in IBC with complete pathological nodal response post-NAC.

Distinct presentation of melanoma in Black patients may inform strategies to improve outcomes.

INTRODUCTION: Melanoma guidelines stem largely from data on non-Hispanic White (NHW) patients. We aimed to identify features of melanoma within non-Hispanic Black (NHB) patients to inform strategies for earlier detection and treatment. METHODS: From 2004 to 2019 Surveillance, Epidemiology, and End Results (SEER) data, we identified nonmetastatic melanoma patients with known TN category and race. Kaplan-Meier cancer-specific survival (CSS) estimates and multivariable Cox proportional hazard modeling analyses were performed. RESULTS: Of 492 597 patients, 1499 (0.3%) were NHB, who were younger (21% vs. 17% age <50) and more commonly female (54% vs. 41%) than NHW, both p < 0.0005. For NHBs, lower extremity was the most common site (52% vs. 15% for NHWs, p < 0.0001), T category was higher (55% Tis-T1 vs. 82%; 27% T3-T4 vs. 8%, p < 0.0001) and stage at presentation was higher (19% Stage III, vs. 6%, p < 0.0001). Within the NHB cohort, males were older, and more often node-positive than females. Five-year Stage III CSS was 42% for NHB males versus 71% for females, adjusting for age and clinical nodal status (hazard ratio 2.48). CONCLUSIONS: NHB melanoma patients presented with distinct tumor characteristics. NHB males with Stage III disease had inferior CSS. Focus on this high-risk patient cohort to promote earlier detection and treatment may improve outcomes.

Neoadjuvant cobimetinib and atezolizumab with or without vemurafenib for high-risk operable Stage III melanoma: the Phase II NeoACTIVATE trial.

Both targeted therapies and immunotherapies provide benefit in resected Stage III melanoma. We hypothesized that the combination of targeted and immunotherapy given prior to therapeutic lymph node dissection (TLND) would be tolerable and drive robust pathologic responses. In NeoACTIVATE (NCT03554083), a Phase II trial, patients with clinically evident resectable Stage III melanoma received either 12 weeks of neoadjuvant vemurafenib, cobimetinib, and atezolizumab (BRAF-mutated, Cohort A, n = 15), or cobimetinib and atezolizumab (BRAF-wild-type, Cohort B, n = 15) followed by TLND and 24 weeks of adjuvant atezolizumab. Here, we report outcomes from the neoadjuvant portion of the trial. Based on intent to treat analysis, pathologic response (≤50% viable tumor) and major pathologic response (complete or near-complete, ≤10% viable tumor) were observed in 86.7% and 66.7% of BRAF-mutated and 53.3% and 33.3% of BRAF-wild-type patients, respectively (primary outcome); these exceeded pre-specified benchmarks of 50% and 30% for major pathologic response. Grade 3 and higher toxicities, primarily dermatologic, occurred in 63% during neoadjuvant treatment (secondary outcome). No surgical delays nor progression to regional unresectability occurred (secondary outcome). Peripheral blood CD8 + TCM cell expansion associated with favorable pathologic responses (exploratory outcome).

Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor-Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination: A Phase 3 Randomized Clinical Trial.

Importance: Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease. Objective: To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone. Design, Setting, and Participants: A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023. Interventions: Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery. Main Outcomes and Measures: The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression). Results: Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], -90.4% [-95.2 to -81.9%] vs -76.7% [-89.0 to -55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%. Conclusions and Relevance: In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT01953588.

Pregnancy-associated melanoma: characteristics and outcomes from 2002 to 2020.

Melanoma diagnosed within 1 year of pregnancy is defined as pregnancy-associated melanoma (PAM). No robust data on how pregnancy influences melanoma nor guidelines for PAM management exist. With IRB approval, female patients with a pathology-confirmed melanoma diagnosis within 1 year of pregnancy treated at our institution from 2000 to 2020 were identified. Controls from the cancer registry were matched 1 : 4 when available on decade of age, year of surgery (±5), and stage. We identified 83 PAM patients with median follow-up of 86 months. Mean age at diagnosis was 31 years. 80% AJCC V8 stage I, 2.4% stage II, 13% stage III, 4.8% stage IV. Mean Breslow thickness was 0.79 mm and 3.6% exhibited ulceration. The mean mitotic rate was 0.76/mm 2 . In terms of PAM management, 98.6% of ESD patients and 86.7% of LSD patients received standard-of-care therapy per NCCN guidelines for their disease stage. No clinically significant delays in treatment were noted. Time to treatment from diagnosis to systemic therapy for LSD patients was an average of 46 days (95% CI: 34-59 days). Comparing the 83 PAM patients to 309 controls matched on age, stage, and year of diagnosis, similar 5-year overall survival (97% vs. 97%, P  = 0.95) or recurrence-free survival (96% vs. 96%, P  = 0.86) was observed. The outcomes of PAM following SOC treatment at a highly specialized center for melanoma care were comparable to non-PAM when matched by clinical-pathologic features. Specialty center care is encouraged for women with PAM.

Repeat sentinel lymph node surgery for locally recurrent breast cancer after prior mastectomy.

BACKGROUND AND OBJECTIVES: Current NCCN guidelines discourage repeat sentinel lymph node (SLN) surgery in patients with local recurrence (LR) of breast cancer following prior mastectomy. This study addresses the feasibility and therapeutic impact of this approach. METHODS: We identified 73 patients managed with repeat SLN surgery for post-mastectomy isolated LR. Lymphatic mapping was performed using radioisotope with or without lymphoscintigraphy and/or blue dye. Successful SLN surgery was defined as retrieval of ≥1 SLN. RESULTS: SLN surgery was successful in 65/73 (89%), identifying a median of 2 (range 1-4) SLNs, with 10/65 (15%) SLN-positive. Among these, 5/10 (50%) proceeded to ALND. In unsuccessful cases, 1/8 (13%) proceeded to ALND. Seven of 10 SLN-positive patients and 50/55 SLN-negative patients received adjuvant radiotherapy. Chemotherapy was administered in 31 (42%) and endocrine therapy in 50 of 57 HR+ patients (88%). After 28 months median follow-up, eight patients relapsed with the first site local in two, distant in five, and synchronous local/distant in one. No nodal recurrences were observed. CONCLUSIONS: SLN surgery for patients with LR post-mastectomy is feasible and informative. This approach appears oncologically sound, decreases axillary dissection rates and may be used to tailor adjuvant radiation target volumes and systemic therapies.

Assessment of the effect of the American Society of Breast Surgery guidelines on contralateral prophylactic mastectomy rates for unilateral breast cancer.

BACKGROUND: In July 2016, the American Society of Breast Surgeons published guidelines discouraging contralateral prophylactic mastectomy for average-risk women with unilateral breast cancer. We incorporated these into practice with structured patient counseling and aimed to assess the effect of this initiative on contralateral prophylactic mastectomy rates. METHODS: We evaluated female patients with unilateral breast cancer undergoing mastectomy at our institution from January 2011 to November 2022. Variables associated with contralateral prophylactic mastectomy and trends over time were analyzed using the Wilcoxon rank sum test or χ2 analysis as appropriate. RESULTS: Among 3,208 patients, (median age 54 years) 1,366 (43%) had a unilateral mastectomy, and 1,842 (57%) also had a concomitant contralateral prophylactic mastectomy. Across all patients, contralateral prophylactic mastectomy rates significantly decreased post-implementation from 2017 to 2019 (55%) vs 2015 to 2016 (62%) (P = .01) but increased from 2020 to 2022 (61%). Immediate breast reconstruction rate was 70% overall (81% with contralateral prophylactic mastectomy and 56% without contralateral prophylactic mastectomy, P < .001). Younger age, White race, mutation status, and earlier stage were also associated with contralateral prophylactic mastectomy. Genetic testing increased from 27% pre-guideline to 74% 2020 to 2022, as did the proportion of patients with a pathogenic variant (4% pre-guideline vs 11% from 2020-2022, P < .001), of whom 91% had a contralateral prophylactic mastectomy. Among tested patients without a pathogenic variant and patients not tested, contralateral prophylactic mastectomy rates declined from 78% to 67% and 48% to 38% pre -and post-guidelines, respectively, P < .001. CONCLUSION: Implementation of specific patient counseling was effective in decreasing contralateral prophylactic mastectomy rates. While recognizing that patient choice plays a significant role in the decision for contralateral prophylactic mastectomy, further educational efforts are warranted to affect contralateral prophylactic mastectomy rates, particularly in the setting of negative genetic testing.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0.

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAFV600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.

Lessons learned from the COVID-19 pandemic: Using telemedicine for pre-operative surgical evaluation in breast disease.

BACKGROUND/OBJECTIVES: The COVID-19 pandemic motivated telemedicine care to decrease potential exposures for both patients and staff. We hypothesized that select breast surgical patients can be successfully evaluated pre-operatively with telemedicine. METHODS: With institutional review board approval, patients with telemedicine surgical consults between 1 March 2020 and 31 August 2020 were identified retrospectively from our prospective breast surgical registry. The frequency of successful pre-operative evaluation using telemedicine alone was assessed, defined as cases in which surgery was completed on the planned day without changes to the surgical plan after physical examination in the pre-operative area. Differences in disease presentation, patient characteristics, and complications were evaluated by whether the first in-person visit occurred on the day of surgery versus the prior. RESULTS: A total of 374 patients underwent breast surgery between 1 March 2020 and 31 August 2020, of which 96 (25.7%) had a telemedicine consultation. After the telemedicine visit, 38 patients (39.6%) had additional in-person visits with the breast surgeon prior to their operative date, and 58 patients (60.4%) did not. Forty-five patients underwent breast-conserving therapies, 41 mastectomies (25 with reconstruction), two axillary dissections, and eight excisional biopsies. All surgeries were completed on the planned operative day, with no changes in surgical plans. Patients with telemedicine only prior to surgery were more likely to speak English (100% vs. 92.1%, p = 0.02) and have lower body mass index (median 24.9 vs. 29.2, p = 0.01). The frequency of in-person pre-operative visits varied significantly by surgeon (p < 0.001). Age, American Society of Anaesthesiologists score, distance from facility, clinical T/N category, surgery type, and complications did not differ between groups. CONCLUSIONS: Telemedicine can be utilized successfully for select breast surgical patients, with the ability to proceed to surgery in the majority of patients without additional in-person visits.

Intermediate-thickness melanoma: A population-based study of surgical quality metrics.

BACKGROUND: Variability in guideline compliance for melanoma lymph node surgery is partially attributable to controversy about patient selection. Prior data has indicated suboptimal practice of sentinel lymph node biopsy and undertreatment of clinically node-positive disease, predating Multicenter Selective Lymphadenectomy Trial II publication. To minimize bias, we studied compliance with lymph node surgery guidelines in T2/T3 (intermediate-thickness) melanoma patients, where the greatest agreement exists. METHODS: T2/T3 and metastasis 0 melanoma cases were identified from 2004 to 2018 Surveillance, Epidemiology, and End Results data. Analysis used Cochran-Armitage test for trends, multivariable logistic regression, and Kaplan-Meier survival estimates. RESULTS: Of 66,319 eligible T2/T3 patients, 57,211 were clinically node negative; 2,191 were clinically node positive; 6,197 were clinical node unreported; and 19,044/66,319 (28.8%) had no lymph node surgery. Among clinically node-negative patients, 36,433 (63.7%) underwent sentinel lymph node biopsy and 31,026 (85.2%) were pathologically node negative; 1,499 clinically node-positive patients (68.4%) had a lymph node dissection. Lymph node dissection rates declined from 2004 to 2018, 79.8% to 32.0% for clinically node-negative/pathologically node-positive patients and 80.4% to 61.2% for clinically node-positive/pathologically node-positive patients (both P < .0001). For clinically node-negative patients, lymph node surgery compliance improved from 63.7% (2004) to 70.4% (2018) (P < .0001). Compliance correlated with younger age, male sex, tumor mitotic rate, and site (extremity > trunk/head/neck) in multivariable analysis and improved 5-year cancer-specific survival (90.0% vs 83.4%) (all P < .0001). CONCLUSIONS: Despite clear guidelines, one-third of intermediate-thickness melanoma patients in a recent cohort did not have recommended lymph node surgery. Lymph node status is a key determinant of the relative benefit of adjuvant systemic therapy and the need for active surveillance of pathologically node-positive/clinically node-negative patients. These data highlighted a clinical care gap. Efforts to improve guideline compliance are a logical strategy to improve cancer outcomes for intermediate-thickness melanoma patients.