Atif J. Khan

PURPOSE: Patients with breast cancer requiring postmastectomy radiation therapy (PMRT) often desire breast reconstruction. Reconstructions can be adversely affected by PMRT, and fear of reconstruction complications has discouraged adoption of short-course radiation therapy used after lumpectomy. To fill the evidence gap, we conducted a noninferiority trial of hypofractionated versus conventional PMRT in patients undergoing breast reconstruction. The primary outcome was reconstruction complication rate, a composite of wound healing, readmission, capsular contracture, unplanned reoperation, and reconstruction failure. METHODS: Women with unilateral invasive breast cancer with planned immediate or delayed reconstruction and PMRT were randomly assigned (1:1) to 50 Gy (25 fractions/5 weeks) or 42.56 Gy (16 fractions/3 weeks). This study was designed with a noninferiority margin of 10%, assuming a 2-year reconstruction complication rate of 25% with conventional PMRT. Randomization was stratified by immediate versus delayed and autologous versus implant-only reconstruction. RESULTS: Between 2018 and 2021, 898 patients enrolled with a median follow-up of 3.9 years; 825 patients were evaluable for the primary end point. The 24-month reconstruction complication rates were 12.3% (52/422) with hypofractionated PMRT and 10.2% (41/403) with conventional PMRT, corresponding to an estimated difference of -2.1% (95% CI, -6.5 to 2.2). The complication rate was higher (regardless of arm) with implant-only versus autologous reconstruction (odds ratio = 1.65). There was no statistically significant difference in 36-month locoregional recurrence rates: 1.5% (95% CI, 0.7 to 3.2) with hypofractionated and 2.2% (95% CI, 1.1 to 4.3) with conventional PMRT. Acute and late toxicity rates were not statistically different. CONCLUSION: A 16-fraction course of hypofractionated PMRT is safe and noninferior to conventional PMRT in women undergoing breast reconstruction after mastectomy.

Background: Artificial intelligence (AI) is being rapidly integrated into oncologic care, yet little is known about how patients perceive these applications. Understanding patient perceptions is critical to ensuring AI applications align with their needs and preferences. Objective: This study aimed to evaluate oncology patients’ attitudes and beliefs on the use of AI across clinical touchpoints in cancer care. Methods: We conducted a cross-sectional survey study with adult oncology patients from September to December 2024. The survey assessed patients’ comfort with AI use across 8 clinical touchpoints of cancer care (eg, screening, diagnosis, treatment) on a 5-point Likert scale (1=very uncomfortable to 5=very comfortable). Patients also rated their concerns about AI, including potential harms related to its use (eg, medical errors, privacy breaches), on a 3-point Likert scale (1=not concerned to 3=very concerned). Results: Of 383 patients approached, 330 (86.2% response rate) participated; 184 (55.9%) were male, 162 (49.4%) were aged 65 years or older, 35 (10.8%) were Black, 40 (12.1%) were Hispanic or Latino, and 233 (72.6%) were actively receiving cancer treatment. Patients were most comfortable with AI use in cancer screening (80.2%) and supportive care applications, including exercise (78.2%), diet (74.8%), and herbs/supplements (72.4%). Patients were least comfortable with AI use to assist with diagnosis (70.4%), symptom management (67.5%), treatment planning (64.8%), and prognosis (61.5%). Nonetheless, about half (49.7%) were at least somewhat concerned with the use of AI in cancer care, most commonly about the loss of human interaction and medical errors. Conclusions: Although the majority of oncology patients had a favorable view of AI in cancer care, nearly half had concerns about potential harms. Incorporating patient perspectives into AI development is essential for patient-centered and high-quality cancer care.

Metaplastic breast cancer (MpBC) treated with standard chemotherapy has low rates of complete pathological response (pCR)(2–23%). In this study, we evaluate the response to neoadjuvant chemo-immunotherapy (NACI) in early-stage MpBC. Thirty-two stage I-III MpBC patients treated with NACI (KEYNOTE-522 regimen) were prospectively enrolled in an institutional rare tumor program. All MpBC were triple negative; most were of chondromyxoid/matrix-producing (12/32, 38%). The majority had stage II (78%) tumors, 12/32 (37.5%) patients completed NACI, 11/32 (34%) progressed during NACI, and in the remaining 9, NACI was discontinued due to side effects. The pCR rate in the entire cohort was 22% (7/32) and it was statistically higher (5/8, 62%) among patients with high ( ≥ 60%) stromal tumor-infiltrating lymphocytes (sTILs) as compared to patients with < 60% sTILs (1/11, 9%). Most patients received adjuvant systemic therapy (capecitabine 16/32, pembrolizumab 20/32). At a median follow-up of 13 months, there were a total of 2 local recurrences, 10 distant recurrences, and 7 deaths. We demonstrated a modest pCR rate in MpBC with the addition of pembrolizumab (22%). Nonetheless, amongst patients with high sTILs, high pCR rates—comparable to those in the KEYNOTE-522 trial—were observed. These findings suggest that sTILs can be used to triage MpBC patients for NACI.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete ASCO and ASTRO disclaimers in Appendix 1 (online only) for more. PURPOSE: This guideline provides recommendations on use of postmastectomy radiation therapy (PMRT) in breast cancer treatment. Updated recommendations detail indications for PMRT in the upfront surgical setting and after neoadjuvant systemic therapy, and provide guidance on appropriate target volumes, dosing, and treatment techniques. METHODS: A multidisciplinary American Society for Radiation Oncology–ASCO–Society of Surgical Oncology task force addressed four key radiation therapy (RT) questions in patients with breast cancer who undergo mastectomy: (1) indications for PMRT after upfront surgery, (2) indications for PMRT after neoadjuvant systemic therapy followed by surgery, (3) appropriate PMRT volumes and dose-fractionation regimens, and (4) treatment techniques. Recommendations were based on a systematic review and created using a predefined consensus-building methodology for quality of evidence grading and strength of recommendation. RECOMMENDATIONS: After upfront mastectomy, PMRT is indicated for most patients with node-positive breast cancer and select patients with node-negative disease. PMRT is also recommended after neoadjuvant systemic therapy for patients presenting with locally advanced disease and for those with residual nodal disease at the time of surgery. PMRT is conditionally recommended for patients with cT1-3N1 or cT3N0 breast cancer with pathologically negative nodes after neoadjuvant systemic therapy (ypN0). When PMRT is delivered, treatment to the ipsilateral chest wall or reconstructed breast and regional lymphatics is recommended, with moderate hypofractionation preferred, but with conventional fractionation approaches acceptable in rare cases. Computed tomography–based volumetric treatment planning with 3-dimensional conformal RT is recommended, with intensity-modulated RT advised when three-dimensional conformal RT is unable to achieve treatment goals. Deep inspiration breath-hold techniques are also recommended for normal tissue sparing. For patients with skin involvement, positive superficial margins, and/or lymphovascular invasion, use of a bolus is recommended, but routine use of tissue-equivalent bolus is not recommended. Additional information is available at www.asco.org/breast-cancer-guidelines .

PURPOSE: AlphaMissense is a new artificial intelligence–based approach to predicting the pathogenicity of missense variants. However, whether its predictions can be directly applied to clinical decision making remains unclear. This study aimed to evaluate the accuracy of AlphaMissense predictions for DNA damage repair (DDR) genes using genomic and clinical characteristics. METHODS: Sequencing data from 56,965 patients with cancer who underwent Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing between April 2015 and March 2023 and data from The Cancer Genome Atlas (TCGA)/Pan-Cancer Analysis of Whole Genomes (PCAWG) were analyzed. AlphaMissense pathogenicity was evaluated in six commonly mutated DDR genes. Missense mutations were classified into three categories on the basis of AlphaMissense and OncoKB: known pathogenic, newly identified pathogenic by AlphaMissense, or benign. RESULTS: In the MSK-IMPACT cohort, 1,182 (17.5%) of 6,743 unique DDR gene missense mutations were newly identified as pathogenic. In breast, ovarian, pancreatic, and prostate cancers, homologous recombination (HR)–deficiency signatures were more common in tumors with new pathogenic missense mutations in BRCA1/2 , PALB2 , and RAD51C than in benign missense mutations (66.7% v 35.2%, P = .021). In the TCGA/PCAWG data set, HR-deficiency signatures were also more frequent in tumors with new pathogenic mutations than in wild-type (46.2% v 19.2%, P = .036). For tumors with POLE missense mutations, there were no significant differences in tumor mutation burden and POLE-associated signatures between new pathogenic and benign mutations. Patients with new pathogenic ATM missense mutations had fewer TP53 mutations (30.5% v 54.6%, P < .001) and showed improved irradiated tumor control (hazard ratio, 0.58 [95% CI, 0.35 to 0.95]; P = .03) compared with those with benign missense mutations. CONCLUSION: Our findings suggest that AlphaMissense can help identify previously unknown pathogenic DDR gene mutations, but its accuracy is gene-dependent. AlphaMissense prediction still requires additional confirmation with clinical and functional validation.

Background: Mutations in genes encoding DNA repair factors, which facilitate mismatch repair, homologous recombination, or DNA polymerase functions, are known to enhance tumor immunogenicity. Ataxia telangiectasia mutated (ATM) is a central regulator of DNA double-strand break repair and is frequently affected by somatic or germline mutations in various cancer types, including breast, prostate, pancreatic, and lung cancer. However, the consequences of ATM loss on tumor immunogenicity are poorly understood. Methods: We generated isogenic ATM-null models using CRISPR in murine triple-negative breast (4T1) and colorectal (CT26) cancer cell lines. ATM inactivation was confirmed by PCR and western blot. Immune cell infiltrates were assessed by flow cytometry and immunohistochemistry in both murine tumors and human samples from breast and lung cancers (via The Cancer Genome Atlas and institutional cohorts). In vivo, the impact of ATM loss on tumor growth and response to immune checkpoint blockade (anti-programmed cell death protein-1 (PD-1)) was evaluated. Furthermore, we compared the effects of different DNA-damaging agents—including an ATR inhibitor (RP-3500), a PARP inhibitor (olaparib), and the topoisomerase II inhibitor etoposide—on interferon-stimulated gene (ISG) expression and immune modulation. Results: We find that—in contrast to other DNA repair defects—ATM deficiency (1) fails to encourage immune effector cell infiltration into tumors, and (2) does not enable immune cell recruitment via synthetic lethality strategies in clinical trials, such as with ATR inhibition. Assessing various DNA-damaging agents in Atm null tumors revealed a differential activation of type I interferon (IFN) signaling, with etoposide, a topoisomerase II inhibitor, emerging as the strongest activator of ISG under these conditions. Yet, PD-1-targeted immune checkpoint blockade does not bolster the therapeutic activity of etoposide in Atm-null syngeneic tumor models, nor does it modify the tumor microenvironment, suggesting that type I IFN signaling alone is insufficient to overcome immunosuppression in immunologically cold ATM null neoplasms. Conclusions: ATM deficiency, while compromising DNA repair and enhancing sensitivity to radiation and ATR inhibition, does not increase tumor antigenicity or immunogenicity. Altogether, our results have important implications for the design of novel combination therapies for ATM null tumors and highlight the importance of antigenicity in the immunological consequences of defective DNA repair.