Hieken, Tina J.

Abstract Introduction: Hormone receptor positive (HR+), HER2- breast cancer (BC) is the most common subtype of BC. Despite advances in chemotherapy and endocrine therapy optimization, local and systemic recurrences frequently occur, especially for patients with node-positive disease. Recent data suggest a subset of patients with this tumor phenotype may benefit from the addition of anti-Programmed Death-1(aPD1) to neoadjuvant chemotherapy. However, T-cell infiltration (TCI), a biomarker of response to aPD1 and chemotherapy, is typically low in this BC subtype. Preclinical models show that combining preoperative radiation therapy (preop RT) with immune checkpoint inhibitors can enhance TCI and anti-tumor immunity. We conducted the first randomized trial to test whether no-, low- or high-dose RT combined with aPD1 increases TCI and improves responses in non-irradiated, metastatic lymph nodes in HR+/HER2- BC (NCT04443348). Materials & Methods: Eligible patients had ER and/or PR≥10%, HER2 negative invasive BC with clipped and biopsy-proven positive axillary node(s), cT1c-T4c, cN1-3, and at least one of the following criteria: grade 3 or grade 1-2 with cN2-N3, Ki67 >20%, or high genomic assay score. Between 2022-2024, 51 patients from 10 centers were randomized to no (0Gy; control arm), low (9Gy) or high (24Gy) doses of preop RT to the primary tumor with concurrent pembrolizumab followed by a 2-week tumor biopsy. Stratification factors were T1c vs. T2-4 and N1 vs. N2-3. Patients subsequently received pembrolizumab with 12 weeks of paclitaxel, followed by 4 cycles of adriamycin-cyclophosphamide (q2wk or q3wk) with pembrolizumab (200 mg q3 wks or 400 mg q6 wks). Surgery and adjuvant therapy followed standard-of-care. Dual co-primary endpoints were 2wk tumor TCI and nodal pathologic complete response (ypN0) at time of definitive surgery. TCI was assessed by multiplex immunofluorescence (pan-cytokeratin, CD3, CD8), using a rank-based Immunoscore (range 0-1), compared to baseline reference biopsies via two-tailed Mann-Whitney test. ypN0 was evaluated non-comparatively. Secondary endpoints included pCR and Residual Cancer Burden (RCB) 0/1. Results: Among 51 patients enrolled, 49 were evaluable for TCI and 48 for the ypN0 endpoint. Median age was 49.5 years (range 23-78). The cohort had a high-risk clinical profile: 92% had cT2-4, 50% N2-3, and 62% grade 3 tumors. Median ER and PR positivity were 90% (20-100) and 68% (1-98), respectively. Multifocal or multicentric tumors were present in 32%. TCI was assessed at 2 weeks post-treatment. The proportion of tumors with TCI in the upper quartile increased with RT dose escalation: 31% (0Gy), 40% (9Gy), and 53% (24Gy). Median TCI scores at 2 weeks were 0.60 (0Gy), 0.56 (9Gy), and 0.82 (24Gy), compared to a median baseline value of 0.50 from untreated reference samples. A statistically significant increase in TCI was observed only in the 24Gy cohort relative to the untreated group (p=0.027). 70.8% underwent mastectomy, with 39.6% receiving immediate reconstruction. 8% experienced G2/3 wound complications, balanced across arms. Median number of lymph nodes removed was 6.5 (1-42). The overall ypN0 rate was 29%, and 24%(0Gy), 29%(9Gy) and 33%(24Gy) per arm. pCR/RCB 0-1 rates were 18%/27% in the entire cohort and 6%/18%(0Gy), 29%/29%(9Gy), and 19%/33%(24Gy), respectively. Conclusion: The addition of 24Gy preop RT to aPD1 significantly increased tumor TCI in HR+/HER2- early-stage BC. Non-irradiated nodal response rates were promising despite over one-third of the study population with grade 1/2 tumors and high disease burden, laying the foundation for a future randomized trial comparing the efficacy of this novel approach against standard of care for node-positive HR+/HER2- BC. Citation Format: G. Gupta, A. Y. Ho, F. Gharibpoor, Y. Abdou, J. D. Anampa, R. C. Blitzblau, B. C. Calhoun, D. L. Casey, S. F. Dent, L. A. Carey, J. R. Bellon, L. E. Warren, J. Lu, T. J. Hieken, A. G. Taghian, A. Bardia, T. Traina, G. Plitas, K. Gallagher, K. Daugherty, A. Thompson, I. Krop, A. Wolff, E. Mittendorf, J. Fox, H. Garber, E. Hwang, A. J. Khan, J. P. Loene, R. Mutter, S. Patil, C. Santa-Maria, B. V. Vincent, J. L. Wright, L. Spring.Primary Results from the HR+/HER2- Cohort of TBCRC-053 (P-RAD): A Randomized Trial of No, Low, or High Dose Preoperative RADiation with Pembrolizumab and Chemotherapy in Node-Positive, HER2-Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS2-05.

BACKGROUND: The Commission on Cancer (CoC) implemented 6 operative standards to reduce technical variation in cancer surgery. Although designed to guide surgeons in performing key oncologic techniques, these standards also provide a framework for teaching high-quality cancer surgery to trainees. We assessed surgical trainees’ familiarity with the CoC Operative Standards and the underlying principles of cancer surgery to identify knowledge gaps and opportunities for improved education. STUDY DESIGN: The American College of Surgeons Cancer Surgery Standards Program distributed an anonymous survey to general surgery residents and surgical fellows across the US. Questions addressed the CoC Operative Standards and cancer surgery principles, with scores calculated on the basis of correctness. Univariate logistic regression evaluated associations between trainee or program characteristics and knowledge. Trainees were also asked about their role in procedural documentation, given the synoptic operative report requirements of the standards. RESULTS: A total of 244 surveys were completed by 205 residents and 39 fellows. Fellows reported greater familiarity with the CoC Operative Standards (68% vs 24%, p < 0.001). Only 30% of trainees reported receiving a formal curriculum on the standards. Correct response rates were 30% for CoC Operative Standards questions vs 50% for cancer surgery principles, with minimal association between knowledge and trainee or program characteristics. Most residents (71%) reported contributing to operative documentation. CONCLUSIONS: Surgical trainees demonstrated limited knowledge of the CoC Operative Standards, highlighting the need for multifaceted educational strategies at the national and institutional levels. Incorporating education about the CoC Operative Standards into surgical training can help emphasize the importance of performing and documenting critical elements of cancer operations.

Background: Circulating tumor DNA (ctDNA) is predictive of recurrence in resected stage III melanoma, yet its role in the neoadjuvant setting for clinical stage III (cSIII) is unclear. Objective: Assess the association between ctDNA and outcomes following neoadjuvant immunotherapy (IO) + targeted therapy (TT) in cSIII melanoma. Design: Patients in the NeoACTIVATE study were treated with neoadjuvant IO + TT, underwent lymphadenectomy, and received adjuvant immunotherapy. Methods: Patients with ctDNA testing performed at baseline, pre- and post-operation were analyzed. Baseline positron emission tomography–computed tomography volumetrics and surgical, major pathological responses (MPR) were assessed. Results: Thirteen patients had serial ctDNA, 10 (77%) were detectable at baseline, and 9/10 (90%) had ctDNA clearance. Seven (54%) achieved MPR, all with undetectable preoperative ctDNA, yet 3/7 (43%) had disease recurrence. Conclusion: ctDNA and MPR are poor predictors of recurrence following neoadjuvant IO + TT for cSIII melanoma patients. Further studies are warranted to define the role of ctDNA in this setting.

Abstract Background Partial breast irradiation (PBI) is an effective treatment for early-stage breast cancer. However, evidence comparing different PBI modalities is limited. Methods This trial emulation uses electronic health records from a multi-state large tertiary health system. Three PBI modalities were compared: proton radiation therapy, photon radiation therapy, and applicator-based brachytherapy. Inverse probability weighting (IPW) was used to balance confounders. The primary outcome was ipsilateral breast recurrence (IBR). Results Between 2013 and 2023, 1041 women with early-stage breast cancer were treated with PBI. Of these, 1026 patients were included in the analyses. The median age was 66 years; 22.51% had ductal carcinoma in situ (DCIS), and 97.56% were estrogen receptor positive. With median follow-up of 38.2 months, the rate of IBR in the overall group was 3.05% (95% confidence interval [CI] = 1.99% to 4.65%) at 3 years. After IPW, compared with photon PBI, the hazard ratio for IBR for proton PBI was 2.11 (95% CI = 0.70 to 6.33) and for brachytherapy, 3.86 (95% CI = 1.39 to 10.69). Compared with proton PBI, the hazard ratio for IBR for brachytherapy was 1.83 (95% CI = 0.88 to 3.81). IBR risk was similar across PBI modalities for patients with tumor size ≤ 10 mm and in patients treated for DCIS. Among patients with tumor size &gt;10 mm, the hazard ratio for IBR for brachytherapy was 7.64 (95% CI = 1.64 to 35.58) and 3.59 (95% CI = 1.22 to 10.56) relative to photons and protons, respectively. Conclusion PBI with applicator-based brachytherapy was associated with higher IBR than photon or proton PBI in patients with tumor size &gt; 10 mm, suggesting the need for more careful PBI patient selection for this modality.

Importance Contemporary guidelines recommend sentinel lymph node biopsy (SLNB) for patients with melanoma with predicted risk of SLN metastasis greater than 10% and consideration of SLNB when the risk is 5% to 10%. A gene expression profile (GEP)–based test that can accurately identify patients with a low risk of SLN metastasis would refine selection for SLNB. Objective To establish the predictive capability of the combined clinicopathological factors and GEP (CP-GEP) test to identify patients with primary cutaneous melanoma who can safely forgo SLNB and to investigate the prognostic value of CP-GEP regarding the outcome in patients with cutaneous melanoma after a negative SLNB (not reported herein). Design, Setting, and Participants This prognostic study was conducted from September 2021 to June 2024 at 9 academic medical centers with experienced melanoma surgeons. Included were patients with biopsy-proven invasive cutaneous melanoma with T1 to T3 tumors and clinically negative regional LNs. All patients were deemed candidates for SLNB using standard clinical criteria. GEP was performed on formalin-fixed, paraffin-embedded tissue from the primary melanoma biopsy. Analyses were performed from December 2024 to August 2025. Intervention CP-GEP testing to determine risk of having a positive SLNB in patients with T1 to T3 cutaneous melanoma who were considered appropriate candidates for the procedure based on standard clinical parameters. Main Outcomes and Measures CP-GEP results were reported as low risk or high risk; the primary outcome measure was negative predictive value (NPV) in low-risk cases. Analyses included NPV assessment by tumor (T) subcategory, primary site, and age. Results A total of 1761 patients (median [IQR] age, 64 [53-72] years; 997 male [56.6%]) underwent SLNB (310 [17.6%] SLN positive) and had a successful CP-GEP test; GEP was successful in 97.7% of samples. A total of 651 patients (37.0%) were considered low risk by CP-GEP. Among low-risk cases, 46 (7.1%) were SLN positive, and NPV was 92.9% (95% CI, 90.7%-94.8%). High-risk cases had a 23.8% (264 of 1110) SLN-positive rate. The percentage of cases with low-risk CP-GEP declined with increasing T category (T1 = 346 of 507 [68.2%]; T2 = 295 of 897 [32.9%]; T3 = 10 of 357 [2.8%]). CP-GEP results were consistent in discriminating SLN-positive rates across primary sites, histologic subtypes, and mitotic count categories. In 2 large subsets, clinical stage IB (n = 1187) and patients 65 years and older (n = 832), 6.5% (95% CI, 4.6%-8.8%) of low-risk clinical stage IB cases and 6.6% (95% CI, 4.2%-9.7%) of all low-risk cases in patients 65 years and older were SLN positive vs 18.3% (95% CI, 15.3%-21.6%) and 20.3% (95% CI, 16.8%-24.2%) for high-risk cases, respectively. Conclusions and Relevance In this multicenter, prospective, blinded, prognostic study, the CP-GEP test reliably identified patients with melanoma with less than 10% SLN metastasis risk. SLN metastasis rates were approximately 3-fold greater for high-risk vs low-risk CP-GEP cases. In appropriately selected patients, the CP-GEP test may add value for shared patient-surgeon decision-making.

Neuroendocrine carcinomas of the breast are a rare subtype of invasive breast carcinomas, and those with morphologic and immunophenotypic features supporting Merkel cell carcinoma (MCC) are even more rare. Accurate diagnosis of these entities is important for clinical decision-making regarding the selection of optimal treatments. We report a patient withMCC in the deep breast parenchyma of a 52-year-old woman, without evidence of a cutaneous component. This tumor exhibited characteristic morphologic and immunophenotypic features of MCC, including sheets of high grade, hyperchromatic tumor cells, with perinuclear dot-like staining of keratin 20. To our knowledge, this is the sixth report of parenchymal breast MCC, and due to its rarity and aggressive course, we reviewed the literature, including prior experience on its diagnosis and management.

ABSTRACT Background and Objectives Neoadjuvant chemoimmunotherapy (NACI) for node‐positive breast cancer may induce immune cell activation in regional lymph nodes (LN), confounding post‐NACI imaging. Here we evaluated RECIST 1.1 criteria to predict post‐NACI pathologic LN status. Methods We studied patients with biopsy‐proven cN+ non‐distant metastatic breast cancer receiving NACI operated on 03/2020–09/2024 with both pre‐ and post‐NACI cross‐sectional imaging. Per RECIST 1.1, LN short axis diameter (SAD) was measured in target (defined as SAD ≥ 15 mm) and nontarget (SAD 10–14.9 mm) LNs. Groups were compared using Fisher′s exact test. Results 75 patients, median age 53 years, were studied: 61% cN1, 12% cN2, and 27% cN3. Baseline median number of imaging‐suspicious LN was 4 (IQR 2‐5). Post‐NACI, 64% had a nodal pathologic complete response (pCR/ypN0). 55% met RECIST 1.1 LN assessment criteria. 21 of 32 (66%) with an imaging CR (iCR) were ypN0, while 8 of 9 (89%) without an iCR were ypN0. Neither target ( p = 0.24) nor combined target/nontarget LN iCR ( p = 0.76) predicted ypN status. Nodal pCR rates were higher in those with ≤ 1 versus > 1 suspicious LN post‐NACI (71% vs. 42%, p = 0.03). Conclusions RECIST 1.1 criteria did not predict nodal pCR for NACI‐treated node‐positive breast cancer patients. Other post‐NACI imaging assessment strategies are needed.

BACKGROUND: To reduce technical variation in cancer surgery, the Commission on Cancer (CoC) recently implemented 6 operative standards as part of its national cancer center accreditation process. CoC sites are evaluated for compliance with these standards through scheduled visits conducted by trained site reviewers. We characterized site reviewers’ perspectives on the implementation of the operative standards. STUDY DESIGN: Twenty interviews were conducted with CoC site reviewers using a semistructured interview guide based on the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. Themes were identified using thematic analysis mapped to the updated Consolidated Framework for Implementation Research. RESULTS: Site reviewers viewed the operative standards as an effective starting point for improving technical quality and were optimistic the standards would lead to positive change. Compliance was associated with supportive site leadership, effective interdisciplinary communication, and the availability of adequate personnel and institutional resources. In contrast, resistance from surgeons was identified as a key barrier. CoC site reviewers interpret their role as extending beyond assessing compliance, viewing themselves as advocates, educators, and partners to the sites. CONCLUSIONS: Overall, CoC site reviewers perceive the operative standards favorably. To enhance implementation of the operative standards, efforts should focus on modifiable institutional and individual-level factors, such as leadership support and surgeon engagement. Additionally, the multifaceted role of the site reviewers presents a valuable opportunity to improve compliance by formalizing the supportive relationship between reviewers and sites.

Summary: Breast cancer is a common malignancy, and treatment often involves mastectomy. For oncological safety, the anterior and lateral cutaneous branches of the third through fifth intercostal nerves are routinely resected during nipple-sparing mastectomies, leading to loss of nipple sensation. The current gold standard for nipple neurotization uses nerve allografts to connect the nipple with a remaining stump of an intercostal nerve. Despite the convenience of off-the-shelf solutions, this study explored a novel approach using intercostal nerves as autografts or for direct repair to restore nipple sensation. Six patients underwent nipple-sparing mastectomy and opted for nipple neurotization. Three patients underwent neurotization with an intercostal nerve autograft, whereas in 3 patients, long intercostal nerves allowed nipple neurotization directly without the need for an autograft. Meticulous dissection of the intercostal nerves enabled a length of approximately 9 cm (±1.5) per nerve. The acquired nerve length allowed tension-free coaptation of direct nipple neurotization in 3 patients and utilization as an autograft in the other 3 patients. No postoperative complications were observed, whereas sensory outcomes are yet to be evaluated. The study highlighted the feasibility of using intercostal nerves either as autologous intercostal nerve grafts or for direct neurotization. Using an intercostal nerve as an autograft is a cost-effective and time-efficient strategy to avoid the need for an allograft without additional donor-site morbidity. This technique offers a practical and globally accessible solution for improving patient access to state-of-the-art postmastectomy breast reconstruction.