Faculty Bibliography

PURPOSE:The primary goal was to map the anatomic pattern of isolated nodal recurrences (NR) in the supraclavicular (SCV), axillary, and internal mammary nodes (IMNs) in patients with breast cancer treated with curative-intent surgery with or without radiation therapy (RT). Secondary objectives were to assess clinical and pathologic factors associated with patterns of NR and survival rates. METHODS AND MATERIALS:Patients with NR after treatment at a single cancer center during 1998 to 2013 were identified. Patients with prior distant metastases or NR without correlative imaging were excluded. All NRs were overlaid onto representative axial computed tomographic images. Multivariable analysis was performed to identify clinical and pathologic characteristics associated with NR. Kaplan-Meier curves were generated to assess the rate of relapse by nodal region according to pathologic feature or radiation treatment status. RESULTS:The locations of 243 NRs among 153 eligible patients were mapped. The majority of NR occurred in the axilla (42%; 102/243), followed by the IMN (32.5%; 79/243) and the SCV (25.5%; 62/243). Radiation Therapy Oncology Group (RTOG) or European Society for Radiation therapy and Oncology (ESTRO) clinical target volume encompassed 82% (198/243) of NRs. The majority of out-of-field NRs were located in the lateral and posterior SCV region for both RTOG (67%; 30/45) and ESTRO (89%; 49/55) guidelines. The high-risk patients who received regional RT to the SCV relapsed at a similar rate in the medial, but a higher rate in lateral SCV (P = .009), compared with low-risk patients who received no nodal RT. Lymphovascular invasion most strongly associated with IMN NR (P = .001); grade 3 disease highly associated with both IMN (P = .001) and SCV NR (P = .02). The presence of an IMN NR portended for significantly inferior overall survival (OS), compared with an axillary NR, with a 5-year OS of 59% versus 72%, respectively (P = .03). CONCLUSIONS:In this 3-dimensional image-based analysis of NR patterns in breast cancer patients treated with contemporary therapies, the lateral and posterior SCV represented a distinct site of NR that is not routinely included within current breast cancer contouring atlases. Grade 3 breast cancer and LVI were most commonly associated with the development of NR in the SCV. Modifying the CTV to encompass the lateral and posterior SCV in patients with breast cancer with these features might be justified.

PURPOSE/OBJECTIVE:The treatment paradigm for uterine clear cell carcinoma is often linked to serous carcinoma. This study compares oncologic outcomes between women with uterine clear cell and serous carcinoma. METHODS AND MATERIALS/METHODS:We reviewed 114 women with stage I-II uterine clear cell carcinoma (n = 17, 15%) or serous carcinoma (n = 97, 85%) who underwent hysterectomy and salpingo-oophorectomy at our institution from April 1992 to December 2011; 86 (76%) had stage IA, 14 (12%) had stage IB, and 14 (12%) had stage II disease. Median followup was 57 months. RESULTS:Patients with uterine clear cell and serous carcinoma did not differ significantly by age ≥60 years, stage, or rate of lymphovascular invasion. There was no difference in the number of patients with clear cell or serous histology who received adjuvant radiotherapy (71% vs. 84%, respectively; p = 0.31); however, significantly fewer patients with clear cell histology received adjuvant chemotherapy (35% vs. 67%, respectively; p = 0.02). At 5 years, there were no significant differences in disease-free survival (94% vs. 84%, respectively; p = 0.27), disease-specific survival (100% vs. 92%, respectively; p = 0.20), or overall survival (100% vs. 89%, respectively; p = 0.34). The differences in chemotherapy utilization did not impact pattern of relapse, specifically peritoneal spread (7% vs. 6%, respectively; p = 0.92) or other distant sites (0% vs. 9%, respectively; p = 0.17). CONCLUSIONS:Oncologic outcomes and recurrence patterns of women with stage I-II uterine clear cell carcinoma compared favorably with those of women with serous carcinoma, despite significantly less adjuvant chemotherapy use. Potential reduction in adjuvant therapy in women with clear cell carcinoma should be studied prospectively.

PURPOSE/OBJECTIVE:Recurrent meningiomas remain therapeutically challenging, often progressive despite multimodality salvage. There are limited data guiding reirradiation (reRT), and proton beam radiation therapy (PBRT) offers a potential advantage owing to lower integral brain dose. PATIENTS AND METHODS/METHODS:We retrospectively conducted a review of 16 patients who received PBRT reRT for recurrent meningiomas. Kaplan-Meier and proportional hazards were used to determine post-PBRT progression-free survival (PFS) and overall survival (OS) and to evaluate clinical predictors. RESULTS: = .049). Overall late grade 3+ toxicity rate was 31%. Two patients (13%) developed radionecrosis at 6 and 16 months after PBRT; only 1 was symptomatic. CONCLUSIONS:This is the first series specifically analyzing PBRT alone as a reRT strategy for recurrent meningioma. We report fair intracranial control with low rates of radionecrosis at 1 year after reRT. However, strategies to achieve durable outcomes are needed, particularly for high-grade tumors.

CONTEXT:Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options. CASE:A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL. MOLECULAR EVALUATION:Both prospective clinical sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation. CONCLUSION:Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.

BACKGROUND:BC in the era of HER2-targeted therapy. PATIENTS AND METHODS:BC with BM who underwent radiation therapy as primary BM treatment from January 2001 to December 2011 at Memorial Sloan Kettering Cancer Center by retrospective review. Patient characteristics at the time of BM diagnosis and their associations with time from BM to death were evaluated by Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. RESULTS:Significantly better survival from BM was noted for patients with higher performance status, fewer BM lesions, continued use of HER2-targeted therapy after BM diagnosis, and better controlled extracranial metastatic disease. Absence of neurologic symptoms at BM diagnosis was significantly associated with fewer lesions, decreased use of whole brain radiotherapy, and longer survival in univariate and multivariate analysis (multivariate hazard ratio, 3.69; 95% confidence interval, 1.69-8.07). CONCLUSION:BC, in terms of improving prognosis, quality of life, and avoidance of whole brain radiotherapy, is warranted.

Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. In vivo production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response.Significance: Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg Cancer Res; 78(14); 3755-60. ©2018 AACR.

PURPOSE:To determine whether phosphatidylinositol-3-kinase (PI3K) mutations confer suboptimal local control after radiation therapy (RT) for brain metastases. METHODS AND MATERIALS:We retrospectively reviewed 259 patients with brain metastases treated with RT during the period 2004 to 2017 for whom tumor genetic data (MSK-IMPACT) were available for primary or metastatic lesions. Associations between clinical factors, PI3K mutations status, and local failure (LF) were evaluated with univariate and multivariate competing risks regression. RESULTS:A total of 112 patients received whole brain radiation therapy (WBRT) to a median dose of 30 Gy in 10 fractions, and 147 patients received stereotactic radiosurgery (SRS) to 338 lesions; 276 lesions were treated with single fraction SRS (median dose 21 Gy) and 76 lesions over 3 to 5 fractions SRS (median dose 30 Gy). PI3K mutations were present in 36 WBRT patients (32%) and 44 SRS patients (30%). For WBRT, patients with PI3K mutations (hazard ratio 2.67, P < .001) were found to be at higher risk for LF on multivariable analysis, and the 1-year cumulative incidence of LF was 50% (95% confidence interval [CI] 32%-65%) for patients with PI3K mutations versus 26% (95% CI 17%-37%) for patients without PI3K mutations. For SRS lesions, while PI3K mutations positivity was not statistically significantly associated with LF, higher rate of LF was observed: 1-year LF cumulative incidence of 11% (95% CI 6%-17%) for patients with PI3K mutations versus 5% (95% CI 3%-9%) for patients without PI3K mutations. CONCLUSION:Patients with PI3K mutations are at higher risk for LF for brain metastases after RT. Novel therapeutic strategies to improve treatment outcomes in these patients should be considered.

OBJECTIVES/OBJECTIVE:Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway has been associated with radioresistance. It is unclear whether such mutations confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT). Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT. METHODS:We retrospectively reviewed 166 patients who underwent SBRT to primary or metastatic lung lesions from 2007-2015 for whom genetic testing data was available for EGFR, AKT, and PIK3CA genes. Association between clinical factors, including molecular mutation status, and LF was evaluated. RESULTS:Six patients (4%) had PIK3CA mutation, 36 patients (22%) had EGFR mutation, and one patient (0.6%) had AKT1 mutation. Median lesion size was 2.0 cm (range, 0.6-5.6 cm); median dose was 48Gy in 4 fractions (range, 30-70Gy in 3-10 fractions). Median follow-up for survivors was 27.3 months (range, 3.8-66.7 months). LF occurred in 16 patients (10%). On univariate analysis, PIK3CA mutation was associated with LF (HR 10.44 [95% CI 2.16-50.46], p=0.003), while tumor histology, tumor size, primary tumor site, BED and EGFR mutation were not. At one year, probability of LF in lesions with PIK3CA mutation was 20.0% vs. 2.9% in lesions without mutation (p<0.001 by log rank test). CONCLUSION/CONCLUSIONS:Although the number of patients affected was small, PIK3CA mutation was significantly associated with higher risk of LF in patients undergoing lung SBRT. This association has not previously been reported for lung SBRT and indicates the need for further validation.

IMPORTANCE/OBJECTIVE:Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. As systemic therapies improve, patients with lung cancer live longer and thus are at increased risk for brain metastases. Understanding how prognosis varies across this heterogeneous patient population is essential to individualize care and design future clinical trials. OBJECTIVE:To update the current Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with non-small-cell lung cancer (NSCLC) and brain metastases. The DS-GPA is based on data from patients diagnosed between 1985 and 2005, and we set out to update it by incorporating more recently reported gene and molecular alteration data for patients with NSCLC and brain metastases. This new index is called the Lung-molGPA. DESIGN, SETTING, AND PARTICIPANTS/METHODS:This is a multi-institutional retrospective database analysis of 2186 patients diagnosed between 2006 and 2014 with NSCLC and newly diagnosed brain metastases. The multivariable analyses took place between December 2015 and May 2016, and all prognostic factors were weighted for significance by hazard ratios. Significant factors were included in the updated Lung-molGPA prognostic index. MAIN OUTCOMES AND MEASURES/METHODS:The main outcome was survival. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. Log rank tests were used to compare adjacent classes and to compare overall survival for adenocarcinoma vs nonadenocarcinoma groups. RESULTS:The original DS-GPA was based on 4 factors found in 1833 patients with NSCLC and brain metastases diagnosed between 1985 and 2005: patient age, Karnofsky Performance Status, extracranial metastases, and number of brain metastases. The patients studied for the creation of the DS-GPA had a median survival of 7 months from the time of initial treatment of brain metastases. To design the updated Lung-molGPA, we analyzed data from 2186 patients from 2006 through 2014 with NSCLC and newly diagnosed brain metastases (1521 adenocarcinoma and 665 nonadenocarcinoma). Significant prognostic factors included the original 4 factors used in the DS-GPA index plus 2 new factors: EGFR and ALK alterations in patients with adenocarcinoma (mutation status was not routinely tested for nonadenocarcinoma). The overall median survival for the cohort in the present study was 12 months, and those with NSCLC-adenocarcinoma and Lung-molGPA scores of 3.5 to 4.0 had a median survival of nearly 4 years. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:In recent years, patient survival and physicians' ability to predict survival in NSCLC with brain metastases has improved significantly. The updated Lung-molGPA incorporating gene alteration data into the DS-GPA is a user-friendly tool that may facilitate clinical decision making and appropriate stratification of future clinical trials.

BACKGROUND AND PURPOSE:Hypofractionated conformal radiotherapy (hfCRT) is used for larger brain metastases or metastases near critical structures. We investigated hfCRT outcomes for newly diagnosed brain metastases. MATERIALS AND METHODS:We identified 195 patients with 1-3 brain metastases who underwent 5×6Gy hfCRT for 231 lesions from 2007 to 2013. Associations among clinical factors, local control (LC), distant brain control (DC) and overall survival (OS) were tested using univariate and multivariate (MVA) Cox regression analysis and Kaplan-Meier method. RESULTS:Median follow-up was 12.8months. One hundred forty-three (62%) lesions were treated with hfCRT post-operatively, and 88 (38%) with definitive hfCRT. LC for all lesions was 83% at 1year. For lesions treated with post-operative hfCRT, tumor size (HR=4.7, p=0.04) and subtotal resection (HR=2.7, p=0.02) were predictive of local failure on MVA. For lesions ≥2.8cm in size, LC was 61% at 12months for lesions status-post subtotal resection, compared to 84% status-post gross total resection (p=0.004). Extracranial disease presence was associated with worse DC (HR=1.8, p=0.008) and OS (HR=3.1, p<0.001). CONCLUSIONS:We showed 5×6Gy hfCRT provides acceptable LC at 1year for limited brain metastases. For large lesions not grossly resected, more aggressive strategies can be considered to improve LC.