Tyrosine Kinase Inhibitors With and Without Up-Front Stereotactic Radiosurgery for Brain Metastases From EGFR and ALK Oncogene-Driven Non-Small Cell Lung Cancer (TURBO-NSCLC).

PURPOSE: Newer-generation tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements have demonstrated high CNS activity. The optimal use of up-front stereotactic radiosurgery (SRS) for brain metastases (BM) in patients eligible for CNS-penetrant TKIs is controversial, and data to guide patient management are limited. MATERIALS AND METHODS: Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs with and without up-front SRS were retrospectively collected from seven academic centers in the United States. Time-to-CNS progression and overall survival (OS) were analyzed, with multivariable adjustment in Fine & Gray and Cox proportional hazards models for clinically relevant factors. RESULTS: From 2013 to 2022, 317 patients were identified (200 TKI-only and 117 TKI + SRS). Two hundred fifty (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients receiving TKI + SRS were more likely to have BM ≥1 cm (P < .001) and neurologic symptoms (P < .001) at presentation. Median OS was similar between the TKI and TKI + SRS groups (median 41 v 40 months, respectively; P = .5). On multivariable analysis, TKI + SRS was associated with a significant improvement in time-to-CNS progression (hazard ratio [HR], 0.63 [95% CI, 0.42 to 0.96]; P = .033). Local CNS control was significantly improved with TKI + SRS (HR, 0.30 [95% CI, 0.16 to 0.55]; P < .001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated a greater benefit from TKI + SRS in patients with BM ≥1 cm in diameter for time-to-CNS progression and CNS progression-free survival. CONCLUSION: The addition of up-front SRS to CNS-penetrant TKI improved time-to-CNS progression and local CNS control, but not OS, in patients with BM from EGFR- and ALK-driven NSCLC. Patients with larger BM (≥1 cm) may benefit the most from up-front SRS.

Satisfaction with Breasts Following Autologous Reconstruction: Assessing Associated Factors and the Impact of Revisions.

BACKGROUND: Autologous breast reconstruction (ABR) may confer higher patient reported outcomes than implant breast reconstruction, but an in-depth examination of factors associated with satisfaction after ABR is lacking. We aimed to determine independent predictors of 1-year Satisfaction with Breasts after ABR and assess the importance of elective procedures on satisfaction. METHODS: A retrospective analysis of patients who underwent abdominal-based ABR between 2010 and 2021 and completed the BREAST-Q Satisfaction with Breasts module at 1-year was performed. Elective procedures comprised of breast revision and nipple areolar complex (NAC) reconstruction. RESULTS: 959 patients were included. Satisfaction with Breasts score improved from 53 (IQR: 44 to 64) preoperatively to 64 (53 to 78) at 1-year postoperatively (p<0.001). Factors significantly associated with decreased postoperative score included lower preoperative scores (ß=0.19 [95% CI: 0.08, 0.31], p=0.001), older age (ß=-0.17 [-0.34, -0.01], p=0.042), Asian race (versus White, ß=-6.7 [-12, -1.7], p=0.008), and a history of psychiatric diagnoses (ß=-3.4 [-6.2, -0.66], p=0.015). Patients who received radiation (ß=-5.6 [-9.0, -2.3], p=0.001) or had mastectomy skin flap/nipple necrosis (ß=-3.8 [-7.6, -0.06], p=0.046) also had significantly decreased scores. Satisfaction with Breasts significantly improved after breast revision procedures (54 [42 to 65] to 65 [54 to 78], p<0.001) and NAC reconstruction (58 [47 to 71] to 67 [57 to 82], p<0.001). CONCLUSION: Multiple independent patient and treatment level factors are associated with lower 1-year Satisfaction with Breasts following ABR. Elective procedures have the potential to improve satisfaction. Understanding these findings is imperative for optimizing clinical decision making and managing expectations.

Defining the Genomic Landscape of Diffuse Sclerosing Papillary Thyroid Carcinoma: Prognostic Implications of RET Fusions.

BACKGROUND: Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is an aggressive histopathologic subtype of papillary thyroid carcinoma. Correlation between genotype and phenotype has not been comprehensively described. This study aimed to describe the genomic landscape of DSPTC comprehensively using next-generation sequencing (NGS), analyze the prognostic implications of different mutations, and identify potential molecular treatment targets. METHODS: Tumor tissue was available for 41 DSPTC patients treated at Memorial Sloan Kettering Cancer Center between 2004 and 2021. After DNA extraction, NGS was performed using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets platform, which sequences 505 critical cancer genes. Clinicopathologic characteristics were compared using the chi-square test. The Kaplan-Meier method and log-rank statistics were used to compare outcomes. RESULTS: The most common mutation was RET fusion, occurring in 32% (13/41) of the patients. Other oncologic drivers occurred in 68% (28/41) of the patients, including 8 BRAFV600E mutations (20%) and 4 USP8 mutations (10%), which have not been described in thyroid malignancy previously. Patients experienced RET fusion-positive tumors at a younger age than other drivers, with more aggressive histopathologic features and more advanced T stage (p = 0.019). Patients who were RET fusion-positive had a significantly poorer 5-year recurrence-free survival probability than those with other drivers (46% vs 84%; p = 0.003; median follow-up period, 45 months). In multivariable analysis, RET fusion was the only independent risk factor for recurrence (hazard ratio [HR], 7.69; p = 0.017). CONCLUSION: Gene-sequencing should be strongly considered for recurrent DSPTC due to significant prognostic and treatment implications of RET fusion identification. The novel finding of USP8 mutation in DSPTC requires further investigation into its potential as a driver mutation.

Outcomes of Conversion Surgery for Patients With Low-Risk Papillary Thyroid Carcinoma.

Importance: The outcomes of patients with low-risk thyroid cancer who undergo surgery following a period of active surveillance (AS) are not well-defined. Objective: To evaluate surgical, pathologic, and oncologic outcomes among patients undergoing conversion surgery (CS) following AS for low-risk papillary thyroid carcinoma. Design, Setting, and Participants: In this cohort study, patients who underwent CS for disease progression were compared with patients who underwent CS without disease progression and with a propensity score-matched cohort of patients who underwent initial surgery (IS). The median (IQR) postsurgical follow-up time was 40.3 (18.0-59.0) months. Patients were treated at a quaternary cancer referral center in the United States. Exposures: Surgery. Main Outcomes and Measures: Surgical complications, pathologic characteristics, overall survival (OS), and recurrence-free survival (RFS). Results: Of 550 patients who underwent AS, 55 (10.0%) had CS, of whom 39 (7.1%) had surgery due to suspected disease progression (median [IQR] age, 48 [39-56] years; 32 [82.1%] female). There were no clinically meaningful differences in rates of surgical sequalae between the progression CS group (12 of 39 [30.7%]) and the nonprogression CS group (7 of 16 [43.8%]) (Cramer V, 0.2; 95% CI, 0.01-0.5). The 5-year OS was 100% (95% CI, 100%-100%) in both the disease-progression CS cohort and the IS cohort. Although the cohort of patients undergoing CS after disease progression was by definition a subset with more aggressive tumor behavior, no clinically meaningful differences were observed in the rates of regional recurrence (2 of 39 [5.1%] vs 0 of 39 patients with IS), local recurrence (0 patients), distant metastasis (0 patients), or disease-specific mortality (0 patients) when compared with the matched IS group. Five-year RFS rates were similar: 100% in the IS group and 86% (95% CI, 70%-100%) in the CS group. Conclusions and Relevance: In this cohort study, CS for suspected disease progression was associated with surgical and oncologic outcomes similar to IS, supporting the feasibility and safety of AS for patients with low-risk papillary thyroid carcinoma.

Nonresponse data in sexual well-being among breast reconstruction patients-who are we overlooking?

BACKGROUND: Missing data can affect the representativeness and accuracy of survey results, and sexual health-related surveys are especially at a higher risk of nonresponse due to their sensitive nature and stigma. The purpose of this study was to evaluate the proportion of patients who do not complete the BREAST-Q Sexual Well-being relative to other BREAST-Q modules and compare responders versus nonresponders of Sexual Well-being. We secondarily examined variables associated with Sexual Well-being at 1-year. METHODS: A retrospective analysis of patients who underwent breast reconstruction from January 2018 to December 2021 and completed any of the BREAST-Q modules postoperatively at 1-year was performed. RESULTS: The 2941 patients were included. Of the four BREAST-Q domains, Sexual Well-being had the highest rate of nonresponse (47%). Patients who were separated (vs. married, OR = 0.69), whose primary language was not English (vs. English, OR = 0.60), and had Medicaid insurance (vs. commercial, OR = 0.67) were significantly less likely to complete the Sexual Well-being. Postmenopausal patients were significantly more likely to complete the survey than premenopausal patients. Lastly, autologous reconstruction patients were 2.93 times more likely to respond than implant-based reconstruction patients (p < 0.001) while delayed (vs. immediate, OR = 0.70, p = 0.022) and unilateral (vs. bilateral, OR = 0.80, p = 0.008) reconstruction patients were less likely to respond. History of psychiatric diagnosis, aromatase inhibitors, and immediate breast reconstruction were significantly associated with lower Sexual Well-being at 1-year. CONCLUSION: Sexual Well-being is the least frequently completed BREAST-Q domain, and there are demographic and clinical differences between responders and nonresponders. We encourage providers to recognize patterns in nonresponse data for Sexual-Well-being to ensure that certain patient population's sexual health concerns are not overlooked.

Analyzing mastectomy and reconstruction weight in immediate autologous breast reconstruction: A preliminary study.

BACKGROUND: This study aims to explore the ideal breast size by assessing the relationship between mastectomy to free flap weight ratio and complications as well as patient-reported outcomes in autologous breast reconstruction (ABR). METHOD: A retrospective review of patients undergoing bilateral immediate ABR with mastectomy and flap weights available was completed. Patients were divided into three groups based on the ratio of mastectomy to flap weights. The patients were grouped as "maintained" if the flap weight was within 10% of the mastectomy weight. Patients with a weight difference greater than 10% were used to declare "downsized" or "upsized." Outcomes included complications and four domains of the BREAST-Q at 1-year postoperatively. RESULTS: Three hundred and fifty-nine patients were included in the analysis, of which 112 were downsized, 91 maintained, and 156 upsized, respectively. Presence of complications did not significantly differ among the groups. At 1-year postoperatively, Sexual Well-being significantly differed (p = 0.033). Between preoperative and 1 year, patients who upsized experienced an improvement in Satisfaction with Breasts by 16 points (p < 0.001), while patients who downsized experienced a decline in Physical Well-being of the Chest by 7 points (p = 0.016). Multivariable linear regression model showed that Sexual Well-being was 13 points lower in the downsized cohort than in the maintained cohort (ß = -13, 95% confidence interval: -21 to -5.4; p = 0.001). CONCLUSION: Although complication rates do not significantly differ between the three cohorts, patients who downsize may have lower Sexual Well-being postoperatively. Surgeons should consider our preliminary findings to counsel patients preoperatively about the predicted breast size and the impact of downsizing on sexual health.

Disparity Reduction in United States Breast Reconstruction: An Analysis From 2005-2017 Using 3 Nationwide Data Sets.

BACKGROUND: Following passage of the Women's Health and Cancer Rights Act (WHCRA), a steady rise in breast reconstruction rates was reported; however, a recent update is lacking. This study aimed to evaluate longitudinal trends in breast reconstruction (BR) rates in the U.S. and relevant sociodemographic factors. METHODS: Mastectomy cases with/without BR from 2005 through 2017 were abstracted from the National Surgical Quality Improvement Program (NSQIP), Surveillance, Epidemiology, and End Results (SEER) Program, and National Cancer Database (NCDB). BR rates were examined using Poisson regression. Multivariable logistic regression analysis of NCDB data was used to identify predictors of reconstruction. Race and insurance distributions were evaluated over time. RESULTS: Of 1,554,381 mastectomy patients, 507,631 (32.7%) received BR. Annual reconstruction rates per 1000 mastectomies increased from 2005 to 2012 (NSQIP: Incidence Rate Ratio (IRR) 1.077; SEER: 1.090; NCDB: 1.092) and stabilized from 2013 to 2017. NCDB data showed that patients who were younger (≤59 years), privately insured, had fewer comorbidities, and underwent contralateral prophylactic mastectomy were more likely to undergo BR (all p<0.001). Over time, the increase in BR rates was higher among Black (252.3%) and Asian (366.4%) patients than White patients (137.3%). BR rates increased more among Medicaid (418.6%) and Medicare (302.8%) patients than privately insured (125.3%) patients. CONCLUSIONS: This analysis demonstrates stabilization in immediate BR rates over the last decade; reasons behind this stabilization are likely multifactorial. Disparities based on race and insurance type have decreased, with a more equitable distribution of BR rates.

Clinical-genomic determinants of immune checkpoint blockade response in head and neck squamous cell carcinoma.

BACKGROUNDRecurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is generally an incurable disease, with patients experiencing median survival of under 10 months and significant morbidity. While immune checkpoint blockade (ICB) drugs are effective in approximately 20% of patients, the remaining experience limited clinical benefit and are exposed to potential adverse effects and financial costs. Clinically approved biomarkers, such as tumor mutational burden (TMB), have a modest predictive value in HNSCC.METHODSWe analyzed clinical and genomic features, generated using whole-exome sequencing, in 133 ICB-treated patients with R/M HNSCC, of whom 69 had virus-associated and 64 had non-virus-associated tumors.RESULTSHierarchical clustering of genomic data revealed 6 molecular subtypes characterized by a wide range of objective response rates and survival after ICB therapy. The prognostic importance of these 6 subtypes was validated in an external cohort. A random forest-based predictive model, using several clinical and genomic features, predicted progression-free survival (PFS), overall survival (OS), and response with greater accuracy than did a model based on TMB alone. Recursive partitioning analysis identified 3 features (systemic inflammatory response index, TMB, and smoking signature) that classified patients into risk groups with accurate discrimination of PFS and OS.CONCLUSIONThese findings shed light on the immunogenomic characteristics of HNSCC tumors that drive differential responses to ICB and identify a clinical-genomic classifier that outperformed the current clinically approved biomarker of TMB. This validated predictive tool may help with clinical risk stratification in patients with R/M HNSCC for whom ICB is being considered.FUNDINGFundación Alfonso Martín Escudero, NIH R01 DE027738, US Department of Defense CA210784, The Geoffrey Beene Cancer Research Center, The MSKCC Population Science Research Program, the Jayme Flowers Fund, the Sebastian Nativo Fund, and the NIH/NCI Cancer Center Support Grant P30 CA008748.