Articles from 2022 to 2023 to Inform Your Cancer Practice: Melanoma.

Modern effective systemic therapy for melanoma includes two important classes of treatment: immune checkpoint inhibitors (ICIs), comprising inhibitors of cytotoxic T-lymphocyte antigen 4, programmed cell death receptor 1, and lymphocyte-activation gene 3; and small molecule BRAF/MEK inhibitor therapy. These treatments have revolutionized the management of patients with advanced melanoma and have dramatically improved clinical outcomes. The melanoma treatment landscape continues to evolve as outcome data from completed trials continue to mature and as newer studies begin to report data. In 2022 and 2023, longer-term follow-up data for established single-agent ICI therapy has been published improving our understanding of both efficacy and durability of treatment responses. A trial of a novel combination ICI therapy has demonstrated enhanced efficacy, and a study examining the order/sequence of ICI therapy versus BRAF/MEK inhibitor therapy for first-line treatment of metastatic melanoma showed that survival is improved when patients start with ICI therapy. As the indications for these therapies have expanded to the adjuvant and neoadjuvant space, we also saw the publication of 5-year results of adjuvant therapy in resected stage III patients, new data on the role of adjuvant therapy in resected stage IIB and IIC patients, and, finally, a practice-changing trial demonstrating improved outcomes using a neoadjuvant approach for patients with macroscopic disease amenable to surgical resection. In this article, we review these articles and highlight key elements for surgical oncologists.

Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial.

BACKGROUND: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial. METHODS: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time. RESULTS: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p < 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p < 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p < 0.0001) and SLN-only increased from 6.9% to 39.2% (p < 0.0001). CONCLUSIONS: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials.

Breast Conservation Surgery and Mastectomy Have Similar Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From 1462 Patients on the Prospective, Randomized I-SPY2 Trial.

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8-4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

Adjuvant Radiation Does Not Affect Locoregional Control Following Resection of Melanoma Satellitosis or In-Transit Disease.

BACKGROUND: This study evaluates the association of adjuvant radiation therapy (RT) with improved locoregional (LR) recurrence for resected melanoma satellitosis and in-transit disease (ITD). MATERIALS AND METHODS: Data were collected retrospectively for resected melanoma satellitosis/ITD from 1996 to 2017. RESULTS: 99 patients were identified. 20 patients (20.2%) received adjuvant RT while 79 (79.8%) did not. Mean follow-up in the RT group was 4.3 years and 4.7 years in the non-RT group. 80% of patients who underwent RT suffered a complication, most commonly dermatitis. Locoregional recurrence occurred in 9 patients (45%) treated with adjuvant RT and 30 patients (38%) in the non-RT group (P = 0.805). Median LR-DFS was 5.8 years in the RT group and 9.5 years in the non-RT group (P = 0.604). On multivariable analysis, having a close or positive margin was the only independent predictor of LR-DFS (HR 3.8 95% CI 1.7-8.7). In-transit disease was associated with improved overall survival when compared to satellitosis (HR 0.260, 95% CI 0.08-0.82). DISCUSSION: The use of adjuvant RT is not associated with improved locoregional control in resected melanoma satellitosis or ITD. Close or positive margin was the only treatment-related factor associated with decreased LR-DFS after surgical resection of satellitosis/ITD.

Integration of Universal Germline Genetic Testing for All New Breast Cancer Patients.

BACKGROUND: The American Society of Breast Surgeons recommends genetic testing (GT) for all women with breast cancer (BC), but implementation and uptake of GT has not been well-described. METHODS: A retrospective chart review was performed for newly diagnosed BC patients or patients with a newly identified recurrence of BC seen in a multidisciplinary clinic (MDBC) who were offered genetic counseling (GC) and GT. RESULTS: The 138 women attending the MDBC had a median age of 54 years and comprised non-Hispanic whites (46%), Asians (28%), Hispanics (17%), blacks (4%), and other (5%). Of the 105 (76%) patients without prior GT, 100 (95%) accepted GC, with 93 (93%) of these 100 patients undergoing GT. The patients meeting the National Comprehensive Cancer Network (NCCN) guidelines for GT were more likely to undergo GT. Testing was performed with a 67- to 84-gene panel, together with an 8- to 9-gene STAT panel if needed. Among 120 patients with reports available, including 33 patients previously tested, 15 (12%) were positive (1 BLM, 1 BRCA1, 3 BRCA2, 1 BRIP1, 1 CFTR, 1 CHEK2, 1 MUTYH, 1 PALB2, 1 PRSS1, 1 RAD50, 1 RET, and 2 TP53), 44 (37%) were negative, and 61 (51%) had an uncertain variant. The median time to STAT results (n = 50) was 8 days. The STAT results were available before surgery for 47 (98%) of the 48 STAT patients undergoing surgery. CONCLUSIONS: New BC patients attending the MDBC demonstrated high rates of acceptance of GC and GT. The combination of GC and GT can offer timely information critical to patient risk assessment and treatment planning.

Oncologic Outcomes of Multi-Institutional Minimally Invasive Inguinal Lymph Node Dissection for Melanoma Compared with Open Inguinal Dissection in the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II).

BACKGROUND: Minimally invasive inguinal lymphadenectomy (MILND) is safe and feasible, but limited data exist regarding oncologic outcomes. METHODS: This study performed a multi-institutional retrospective cohort analysis of consecutive MILND performed for melanoma between January 2009 and June 2016. The open ILND (OILND) comparative cohort comprised patients enrolled in the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) between December 2004 and March 2014.The pre-defined primary end point was the same-basin regional nodal recurrence, calculated using properties of binomial distribution. Time to events was calculated using the Kaplan-Meier method. The secondary end points were overall survival, progression-free survival, melanoma-specific survival (MSS), and distant metastasis-free survival (DMFS). RESULTS: For all the patients undergoing MILND, the same-basin regional recurrence rate was 4.4 % (10/228; 95 % confidence interval [CI], 2.1-7.9 %): 8.2 % (4/49) for clinical nodal disease and 3.4 % (6/179) for patients with a positive sentinel lymph node (SLN) as the indication. For the 288 patients enrolled in MSLT-II who underwent OILND for a positive SLN, 17 (5.9 %) had regional node recurrence as their first event. After controlling for ulceration, positive LN count and positive non-SLNs at the time of lymphadenectomy, no difference in OS, PFS, MSS or DMFS was observed for patients with a positive SLN who underwent MILND versus OILND. CONCLUSION: This large multi-institutional experience supports the oncologic safety of MILND for melanoma. The outcomes in this large multi-institutional experience of MILND compared favorably with those for an OILND population during similar periods, supporting the oncologic safety of MILND for melanoma.

Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor 1 (PD-1) inhibition has demonstrated activity in BCC after prior Hedgehog inhibitor treatment. METHODS: We conducted a multicenter, retrospective analysis of BCC patients treated with PD-1 inhibitor therapy. We examined the efficacy and safety of PD-1 therapy, as well as clinical and pathological variables in association with outcomes. Progression-free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated using Kaplan-Meier methodology. Toxicity was graded per Common Terminology Criteria for Adverse Events V.5.0. RESULTS: A total of 29 patients with BCC who were treated with PD-1 inhibition were included for analysis, including 20 (69.0%) with locally advanced and 9 (31.0%) with metastatic disease. The objective response rate was 31.0%, with five partial responses (17.2%), and four complete responses (13.8%). Nine patients had stable disease (31.0%), with a disease control rate of 62.1%. The median DOR was not reached. Median PFS was 12.2 months (95% CI 0.0 to 27.4). Median OS was 32.4 months (95% CI 18.1 to 46.7). Two patients (6.9%) developed grade 3 or higher toxicity, while four patients (13.8%) discontinued PD-1 inhibition because of toxicity. Higher platelets (p=0.022) and any grade toxicity (p=0.024) were significantly associated with disease control rate. CONCLUSIONS: The clinical efficacy of PD-1 inhibition among patients with advanced or metastatic BCC in this real-world cohort were comparable to published trial data. Further investigation of PD-1 inhibition is needed to define its optimal role for patients with this disease.

Factors associated with relapse-free survival after neoadjuvant chemotherapy for breast cancer at a safety net medical center.

BACKGROUND: This study was designed to assess prognostic factors associated with relapse-free survival (RFS) after neoadjuvant chemotherapy (NAC) for breast cancer. METHODS: A single-institution retrospective analysis was performed including clinical, radiographic, and pathologic parameters for all breast cancer patients treated with NAC from 2015 to 2018. All patients had pre-and post-NAC MRI. RESULTS: For 102 patients, median follow-up was 47.4 months, and the five-year RFS was 74%. The 41 (40%) patients who achieved pathologic complete response (pCR) after NAC had a significantly higher five-year RFS than the 61 not achieving pCR. For 31 patients with triple-negative cancers, the five-year RFS was significantly higher in those achieving pCR vs. no pCR. The 44 (43%) patients who achieved radiographic complete response (rCR) after NAC had similar five-year RFS to the 58 (57%) not achieving rCR. CONCLUSION: pCR, node-negativity after NAC, and triple-negative subtype were prognostic factors associated with relapse-free survival after NAC.

A Phase IIb Randomized Controlled Trial of the TLPLDC Vaccine as Adjuvant Therapy After Surgical Resection of Stage III/IV Melanoma: A Primary Analysis.

BACKGROUND: Melanoma therapy has changed dramatically over the last decade with improvements in immunotherapy, yet many patients do not respond to current therapies. This novel vaccine strategy may prime a patient's immune system against their tumor and work synergistically with immunotherapy against advanced-stage melanoma. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine administered to prevent recurrence in patients with resected stage III/IV melanoma. Patients were enrolled and randomized 2:1 to the TLPLDC vaccine or placebo (empty yeast cell wall particles and autologous dendritic cells). Both intention-to-treat (ITT) and per treatment (PT) analyses were predefined, with PT analysis including patients who remained disease-free through the primary vaccine/placebo series (6 months). RESULTS: A total of 144 patients were randomized (103 vaccine, 41 control). Therapy was well-tolerated with similar toxicity between treatment arms; one patient in each group experienced related serious adverse events. While disease-free survival (DFS) was not different between groups in ITT analysis, in PT analysis the vaccine group showed improved 24-month DFS (62.9% vs. 34.8%, p = 0.041). CONCLUSIONS: This phase IIb trial of TLPLDC vaccine administered to patients with resected stage III/IV melanoma shows TLPLDC is well-tolerated and improves DFS in patients who complete the primary vaccine series. This suggests patients who do not recur early benefit from TLPLDC in preventing future recurrence from melanoma. A phase III trial of TLPLDC + checkpoint inhibitor versus checkpoint inhibitor alone in patients with advanced, surgically resected melanoma is under development. TRIAL REGISTRATION: NCT02301611.

PD-1 inhibition therapy for advanced cutaneous squamous cell carcinoma: a retrospective analysis from the University of Southern California.

PURPOSE: Approximately 5% of patients with cutaneous squamous cell carcinoma (CSCC) may develop recurrent or metastatic disease. The management of such cases is challenging and requires multi-disciplinary care. Immunotherapy using PD-1 inhibition was approved to treat unresectable or metastatic CSCC in 2018. Given limited data regarding clinical outcomes outside of published trials, we describe our experience using this therapy. METHODS: We retrospectively reviewed all patients treated with PD-1 inhibition as therapy for locally advanced, regionally metastatic or distant metastatic CSCC at the University of Southern California. Clinicopathological characteristics, treatment data using PD-1 inhibitors, and outcomes were assessed. RESULTS: Among 26 patients treated with PD-1 inhibition, the objective response rate was 42.3%, with 19.2% of patients having partial response and 23.1% having complete response to therapy. The median progression-free survival was 5.4 months. Median tumor mutational burden (TMB) was higher among responders compared to non-responders (60 vs. 9 Mut/Mb, p = 0.04). Primary CSCC tumor location on the head/neck was also associated with response to PD-1 inhibition (p = 0.04). Two patients with mutations affecting mismatch repair deficiency were noted to have complete response to treatment. No other variables were associated with treatment outcomes. CONCLUSION: PD-1 inhibition produces durable responses among patients with advanced or metastatic CSCC. PD-1 inhibition therapy is well tolerated, but patients should be monitored closely for immune-related adverse events, particularly frail or immune-suppressed patients. Further investigation of potential biomarkers to help identify patients who will derive the most benefit from this therapeutic option is needed.

Treatment and Outcomes of Early Stage Breast Cancer in Patients with Hepatic Dysfunction.

BACKGROUND: There exists a dogma of surgical nihilism for patients with cirrhosis and breast cancer causing de-escalation of surgery and impacting survival. We hypothesized that breast cancer surgery would not result in a significant change in the Model for End-Stage Liver Disease-Sodium (MELD-Na) scores before and after surgery. METHODS: We performed a single institutional retrospective review of medical records between January 2013 and July 2019 of patients with concurrent cirrhosis and breast cancer. We used the nonparametric Friedman test to compare differences in MELD-Na scores. RESULTS: Eight patients with both cirrhosis and breast cancer were identified. Median follow-up was 30.5 mo. Half of the patients had Child-Pugh class A cirrhosis and half had Child-Pugh class B cirrhosis. Six (75%) patients underwent lumpectomy and two (25%) underwent mastectomy. There was no statistically significant difference (P = 0.66) in median MELD-Na score before surgery (16) and after surgery (18). Two (25%) patients experienced postoperative complications. Three patients were listed for liver transplantation. Of three listed patients, two (25%) patients underwent successful liver transplantation after breast surgery. One (12.5%) patient died without transplant. Three (37.5%) patients were alive for more than 5 y after breast cancer diagnosis without evidence of cancer recurrence. The eighth patient has remained breast cancer free for more than 6 mo since her surgery. CONCLUSIONS: Surgery for patients with Child-Pugh class A and B cirrhosis and early stage breast cancer did not result in a significant change in MELD-Na score before and after surgery, suggesting that selected patients may benefit from breast cancer surgery with curative intent.

Does use of axillary ultrasound in clinically node-negative patients receiving neo-adjuvant systemic therapy for breast cancer lead to surgical overtreatment?

Increased use of neo-adjuvant chemotherapy (NAC) for breast cancer has raised uncertainty regarding staging of the axilla, particularly for patients with a clinically negative axillary physical examination (PE). We sought to determine whether axillary ultrasound (AUS) prior to NAC to identify occult nodal disease is beneficial in patients with a clinically negative examination by evaluating the difference in nodal burden on final pathology in those with abnormal vs normal AUS. A retrospective review of an institutional cancer registry identified patients who underwent NAC for breast cancer and had a pretreatment AUS. Differences in the number of positive lymph nodes (PLN) in patients with a normal axillary PE and abnormal vs normal AUS prior to NAC were determined. A total of 120 patients who received NAC had a negative axillary PE prior to treatment. Fifty-three had an abnormal AUS and biopsy-proven lymph node (LN) involvement. In patients with an abnormal AUS, median number of PLNs at surgery was 1 vs 0 for those with a normal AUS (mean difference of 2.12, P < .0001). Of those patients with an abnormal AUS and biopsy-proven LN involvement, 87% underwent axillary lymph node dissection (ALND) and nearly half had no PLN on final pathology (N = 23, 43%). Patients with a clinically negative axilla and an abnormal AUS were more likely to have PLN at the time of surgery. However, almost half of those patients had no residual LN involvement. Routine AUS prior to NAC may lead to more extensive surgical management of the axilla.

Radioactive seed vs wire localization for nonpalpable breast lesions: A single institution review.

The aim of this study was to compare wire localization (WL) and radioactive seed localization (RSL) for nonpalpable breast lesions with regard to margin status, re-excision rate, procedure length, and complications related to localization. A retrospective review of the electronic health records at a single institution was performed. There was no difference in re-excision rate, margin positivity, volume of tissue removed, and complication rate for RSL vs WL (P = 0.9934, P = 0.9934, P = 0.6645, and P = 0.4716 respectively). The only difference was a longer OR time, RSL = 104.408 minutes vs WL = 82.386 minutes. (P = 0.0163). RSL and WL are comparable techniques for localization of nonpalpable breast lesions.

The Emerging Role of Surgery for Patients With Advanced Melanoma Treated With Immunotherapy.

BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has improved survival for patients with metastatic melanoma. The types of disease-response patterns to ICI therapy can be more complex relative to traditional chemotherapy and include mixed responses, pseudoprogression, and oligoprogression. The potential benefit of surgery after incomplete response to ICI therapy has not been explored. The purpose of this study was to explore outcomes of surgery after ICI therapy in patients with metastatic melanoma. METHODS: A retrospective study was conducted at two centers and included patients with melanoma who underwent surgery after treatment with monotherapy or combination therapy with anti-programmed cell death protein (PD) 1 and/or anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 checkpoint blockade. RESULTS: Of 25 patients, nine received anti-CTLA-4 therapy, eight received anti-PD-1 therapy, and eight received both anti-CTLA-4 and anti-PD-1 therapies before surgery. Five patients were treated in the adjuvant setting and developed new lesions, whereas 20 patients were treated for metastatic disease and underwent surgery for persistent disease on imaging after ICI therapy. Twenty-five patients underwent 30 operations without complications. Twenty-seven of 30 masses were confirmed to be melanoma on pathology, one was a desmoid tumor and two were necrosis. At a median follow-up of 14.2 months, 2 patients died, 8 were alive with a known disease, and 15 continued to have no further evidence of disease. CONCLUSIONS: Surgery was well tolerated in this cohort of patients receiving ICI therapy for melanoma. Surgery may benefit select patients with an oligoprogressive disease after ICI therapy. After a mixed response, surgery remains the only definitive method to render some patients free of disease.

Identification of the Thoracic Duct Using Indocyanine Green During Cervical Lymphadenectomy.

BACKGROUND: Injury to the thoracic duct (TD) is the most common complication after a left lateral neck dissection, and it carries a high degree of morbidity. Currently, no routine diagnostic imaging is used to assist with TD identification intraoperatively. This report describes the first clinical experience with lymphangiography using indocyanine green (ICG) during lateral neck dissections. METHODS: In six patients undergoing left lateral neck dissection (levels 2-4) for either thyroid cancer or melanoma, 2.5-5 mg of ICG was injected in the dorsum of the left foot 15 min before imaging. Intraoperative imaging was performed with a hand-held near infrared (NIR) camera (Hamamatsu, PDE-Neo, Hamamatsu City, Japan). RESULTS: In five patients, the TD was visualized using NIR fluorescence, with a time of 15-90 min from injection to identification. Imaging was optimized by positioning the camera at the angle of the mandible and pointing into the space below the clavicle. No adverse reactions from the ICG injection occurred, and the time required for imaging was 5-10 min. No intraoperative TD injury was identified, and no chyle leak occurred postoperatively. For the one patient in whom the TD was not identified, it is unclear whether this was related to the timing of the injection or to duct obliteration from a prior dissection. CONCLUSION: This is the first described application of ICG lymphangiography to identify the thoracic duct during left lateral neck dissection. Identification of TD with ICG is technically feasible, simple to perform with NIR imaging, and safe, making it a potential important adjunct for the surgeon.

Practices and Perceptions Among Surgical Oncologists in the Perioperative Care of Obese Cancer Patients.

BACKGROUND: Obesity and cancer are two common diseases in the United States. Although there is an interaction of obesity and cancer, little is known about surgeon perceptions and practices in the care of obese cancer patients. We sought to characterize perceptions and practices of surgical oncologists regarding the perioperative care of obese patients being treated for cancer. METHODS: A cross-sectional survey was designed, pilot tested, and utilized to assess perceptions and practices of surgeons treating cancer patients. Surgical oncologists were identified using a commercially available database, and Qualtrics® was used to distribute and manage the survey. Statistical analyses were completed by using SPSS. RESULTS: Of the 1731 electronic invitations, 172 recipients initiated the survey, and 157 submitted responses (91.2%). Many surgeons (65.7%) believed that obese patients are more likely to present with more advanced cancers and were more likely than system factors to explain this delayed treatment [t(87) = 4.84; p < 0.001]. Nearly two-thirds of providers (64.5%) reported that obesity had no impact on the timing of surgery; however, one-third of respondents (34.2%) were more likely to recommend preoperative nonsurgical therapy rather than upfront surgery among obese patients. For operations of the chest/abdomen and breast/soft tissue, surgeons perceived obesity to be more related to risk of postoperative than intraoperative complications (chest/abdomen mean 4.13 vs. 3.26; breast/soft tissue 4.11 vs. 2.60; p < 0.001). CONCLUSIONS: One in three surgeons reported that patient obesity would change the timing/sequence of when resection would be offered. Many surgeons perceived that obesity was related to a wide array of intra- and postoperative adverse outcomes.

Heterogeneity in Outcomes of Pathologic T1-2N1 Breast Cancer After Mastectomy: Looking Beyond Locoregional Failure Rates.

PURPOSE: A meta-analysis of 22 randomized trials accrued from 1964 to 1986 demonstrated significantly higher rates of locoregional failure (LRF) and breast-cancer mortality in women with 1-3 positive nodes without postmastectomy radiotherapy (PMRT) after mastectomy (mast.). Recent data demonstrate that PMRT reduces distant metastases (DM) in women with pN1 disease. The challenge today is whether all patients with pathologic T1-2pN1 disease have similar substantial LRF/DM risk that routinely warrants PMRT. METHODS: We reviewed patients with pT1-2N1 breast cancer treated with mast. ± adjuvant systemic therapy without PMRT from 2000 to 2013. The endpoints were LRF and DM rates, estimated by cumulative incidence method. RESULTS: We identified 468 patients with median follow-up of 6.3 years. Most (71%) were estrogen receptor/progesterone receptor + human epidermal growth factor receptor 2 (HER2). There were 269 patients with 1+ node, 140 patients with 2+ nodes, and 59 patients with 3+ nodes. The 6-year LRF/DM rates were 4.1%/8.4%. Patients with 1+, 2+, and 3+ nodes had 6-year LRF of 2.3, 5.1 and 8.9%, respectively (p = 0.13). The 6-year DM rate was higher in patients with 3+ nodes versus 1-2+ nodes: 15.7% versus 7.4% (p = 0.02). Several subgroups had low 6-year LRF and DM rates, including T1/1+ node (0.8%/4.1% LRF/DM) and micrometastases (0%/5.8% LRF/DM). CONCLUSIONS: Patients with pT1-2pN1 represent a heterogeneous group with a wide range of LRF/DM rates. In particular, patients with pT1 tumors and 1 + LN, and patients with micrometastases, had low event rates. These groups would derive small absolute reductions in LRF and DM with addition of PMRT, underscoring the importance of patient selection for PMRT in pT1-2pN1 breast cancer.