Ann Griffin

The Prevalence and Prognostic Value of BRAF Mutation in Thyroid Cancer

Objective:To examine the prevalence of BRAF mutation among thyroid cancer histologic subtypes and determine the association of BRAF mutation with indicators of poor prognosis for papillary thyroid cancer and patient outcome. Summary Background Data:The appropriate extent of surgical treatment, adjuvant therapy and follow-up monitoring for thyroid cancer remains controversial. Advances in the molecular biology of thyroid cancer have helped to identify candidate markers of disease aggressiveness. A commonly found genetic alternation is a point mutation in the BRAF oncogene (BRAF V600E), which is primarily found in papillary thyroid cancer and is associated with more aggressive disease. Methods:BRAF V600E mutation status was determined in 347 tumor samples from 314 patients with thyroid cancer (245 with conventional papillary thyroid cancer, 73 with follicular thyroid cancer, and 29 with the follicular variant of papillary thyroid cancer). Univariate and multivariate analyses were performed to determine the association of BRAF V600E with clinicopathologic factors and patient outcome. Results:The prevalence of BRAF V600E mutation was higher in conventional papillary thyroid cancer (51.0%) than in follicular variant of papillary thyroid cancer (24.1%) and follicular thyroid cancer (1.4%) (P < 0.0001). In patients with conventional papillary thyroid cancer, BRAF V600E mutation was associated with older age (P = 0.0381), lymph node metastasis (P = 0.0323), distant metastasis (P = 0.045), higher TNM stage (I and II vs. III and IV, P = 0.0389), and recurrent and persistent disease (P = 0.009) with a median follow-up time of 6.0 years. Multivariate analysis showed that BRAF V600E mutation [OR (95% CI) = 4.2 (1.2–14.6)] and lymph node metastasis [OR (95% CI) = 7.75 (2.1–28.5)] were independently associated with recurrent and persistent disease in patients with conventional papillary thyroid cancer. Conclusions:BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring.

Clinical and molecular features of papillary thyroid cancer in adolescents and young adults

Age disparities in thyroid cancer incidence and outcome among adolescents and young adults (AYAs) with thyroid cancer are under reported. In this study, the authors compared the molecular and clinical features of papillary thyroid cancer (PTC) in AYAs with the same features among patients in other age groups.

Serum thyroglobulin is a poor diagnostic biomarker of malignancy in follicular and Ḧurthle-cell neoplasms of the thyroid

BACKGROUND Serum thyroglobulin (Tg) is the most accurate biomarker for thyroid cancer recurrence. However, some clinicians measure preoperative Tg as a diagnostic cancer marker despite lack of supporting evidence. We examined whether Tg accurately predicts malignancy in follicular or Hürthle-cell neoplasms. METHODS We reviewed 366 patients who underwent thyroidectomies for follicular/Hürthle-cell neoplasms. We compared Tg in malignant versus benign tumors by univariate and receiver-operator characteristic analyses. We also examined several Tg-derived indices that normalized Tg to known confounding factors including nodule size, thyroid function, and type of Tg assay. RESULTS Thirty-nine patients met inclusion criteria for analysis. There were no differences between malignant (n = 16) and benign (n = 23) lesions in Tg or any of the normalized indexes. Receiver-operator characteristic analysis revealed an area under the curve of .59. Lesions with Tg levels greater than 500 mug/L had a positive predictive value of .75. CONCLUSIONS Tg has poor accuracy for predicting malignancy in follicular or Hürthle-cell thyroid neoplasms.

Mitogen-inducible gene-6 expression correlates with survival and is an independent predictor of recurrence in BRAFV600E positive papillary thyroid cancers

BACKGROUND Mitogen-inducible gene-6 (Mig-6) is an immediate early response gene that negatively regulates signaling. EGFR overexpression and activating mutations in MAPK signaling effectors are common events in papillary thyroid cancer (PTC). The purpose of this study was to determine if Mig-6 expression is associated with EGFR expression or surgical outcomes in PTC. METHODS We determined Mig-6 transcript levels from a microarray in 19 patients with PTC who underwent thyroidectomy. We established a maximally selected cutoff to discriminate Kaplan-Meier survival estimates. For cross-validation, we performed quantitative RT-PCR on resected well-differentiated PTC from an additional 106 patients. RESULTS Mig-6 and EGFR mRNA levels correlated directly (P < .0001). Mig-6 expression above the cutoff of 1.10 (2;-dCt[Mig6-GUS]) was associated with greater survival (P = .008). When this cutoff was applied in the cross-validation, high Mig-6 expression was associated with longer survival (P = .03) and disease-free survival (P = .07). Furthermore, high Mig-6 expression was independently predictive of greater disease-free survival in BRAF(V600E)-positive PTC. CONCLUSION High Mig-6 expression in PTC is associated with favorable outcomes. Mig-6 is a novel tumor suppressor that may be a candidate for targeted cancer therapeutics in patients with PTC refractory to conventional therapy.

Outcomes of Melanoma In Situ Treated With Mohs Micrographic Surgery Compared With Wide Local Excision

Importance Melanoma in situ (MIS) is increasing in incidence, and expert consensus opinion recommends surgical excision for therapeutic management. Currently, wide local excision (WLE) is the standard of care. However, Mohs micrographic surgery (MMS) is now used to treat a growing subset of individuals with MIS. During MMS, unlike WLE, the entire cutaneous surgical margin is evaluated intraoperatively for tumor cells. Objective To assess the outcomes of patients with MIS treated with MMS compared with those treated with WLE. Design, Setting, and Participants Retrospective review of a prospective database. The study cohort consisted of 662 patients with MIS treated with MMS or WLE per standard of care in dermatology and surgery (general surgery, otolaryngology, plastics, oculoplastics, surgical oncology) at an academic tertiary care referral center from January 1, 1978, to December 31, 2013, with follow-up through 2015. Exposure Mohs micrographic surgery or WLE. Main Outcomes and Measures Recurrence, overall survival, and melanoma-specific survival. Results There were 277 patients treated with MMS (mean [SD] age, 64.0 [13.1] years; 62.1% male) and 385 treated with WLE (mean [SD] age, 58.5 [15.6] years; P < .001 for age; 54.8% male). Median follow-up was 8.6 (range, 0.2-37) years. Compared with WLE, MMS was used more frequently on the face (222 [80.2%] vs 141 [36.7%]) and scalp and neck (23 [8.3%] vs 26 [6.8%]; P < .001). The median (range) year of diagnosis was 2008 (1986-2013) for the MMS group vs 2003 (1978-2013) for the WLE group (P < .001). Overall recurrence rates were 5 (1.8%) in the MMS group and 22 (5.7%) in the WLE group (P = .07). Mean (SD) time to recurrence after MMS was 3.91 (4.4) years, and after WLE, 4.45 (2.7) years (P = .73). The 5-year recurrence rate was 1.1% in the MMS group and 4.1% in the WLE group (P = .07). For WLE-treated tumors, the surgical margin taken was greater for tumors that recurred compared with tumors that did not recur (P = .003). Five-year overall survival for MMS was 92% and for WLE was 94% (P = .28). Melanoma-specific mortality for the MMS group was 2 vs 13 patients for the WLE group, with mean (SD) survival of 6.5 (4.8) and 6.1 (0.8) years, respectively (P = .77). Conclusions and Relevance No significant differences were found in the recurrence rate, overall survival, or melanoma-specific survival of patients with MIS treated with MMS compared with WLE.

Long-term survival in AIDS-related primary central nervous system lymphoma

Background. The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. Methods. To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). Results. We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART. Conclusion. Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

Chemotherapy treatment patterns for early-stage breast cancer (ESBC): Decreasing use of anthracycline-based regimens.

141 Background: Anthracyclines (A), given in sequence or combination with other agents, have been the mainstay of adjuvant chemotherapy (CTX) for ESBC for more than two decades. Recent molecular studies have questioned the value of A for lower risk disease. A single prospective trial presented in 2005 and published in 2006 (Jones et al) compared docetaxel and cyclophosphamide (TC) to doxorubicin and cyclophosphamide and reported improved disease free survival (2006) and overall survival (2009) with TC. We sought to understand the impact of this study on the type of CTX regimens used to treat ESBC. METHODS Using the UCSF Cancer Registry database and including patients who received at least one cycle of CTX at UCSF, we recorded use of A or non-anthracycline (NA) based CTX regimens in women with ESBC and correlated type of CTX with tumor stage, receptor status, and age. Based on the publication date of TC we looked at the use of A versus NA based CTX during two time periods, 2000-2005 and 2006-2010. RESULTS 1,116 patients met criteria for inclusion; 17 were excluded due to inadequate information. Patient characteristics were: median age 49 (range 21-78), stage I (24%), stage II (56%), and stage III (20%), 50% hormone receptor (HR) +, 25% HER2 +, 17% HR-/HER2-. From 2000-2010, 80% received A CTX. Overall use of A decreased from 95% to 65%, while use of NA based CTX increased from 5% to 35%. The table compares use of NA CTX during the two time periods by clinical variables. CONCLUSIONS Use of NA CTX increased significantly over the 2nd half of the last decade in all cases except those patients with stage III disease. The timing of this marked change correlates with publication of TC, and emphasizes the impact of positive phase III trials on treatment practice. This study was supported by the UCSF Cancer Registry. [Table: see text].

Abstract 4558: FDG-PET uptake in breast cancer molecular subtypes

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Data on breast cancer FDG uptake in relation to clinically relevant molecular subtypes and their interaction is scarce. Some have shown higher standardized uptake values (SUV) in triple negative (TN) and HER2+ than hormone receptor (HR)+ disease. We hypothesize that FDG uptake in HER2+ disease depends on HR status. Methods: We identified 186 invasive breast cancer patients with a whole body FDG-PET/CT scan between 2005 and 2010 at UCSF (within 6 months prior to or after diagnosis but before therapy). Receptor expression was assessed on adjuvant therapy naive specimens using IHC (HR [ER and PR], HER2) and FISH (HER2) according to clinical practice. We related routinely assessed (log-transformed) SUVmax to receptor expression with linear regression and analysis of covariance (ANCOVA), and adjusted for tumor grade. Results: SUVmax was reported for 160 primary breast cancers and 154 had complete data for HR and HER2. Median age at diagnosis was 52 years (range 21-87), and 34% had localized, 52% regional, and 14% distant disease. Average tumor size was 3.9 cm (SD 2.2), and 12% had good, 51% moderate and 37% poor grade. FDG uptake strongly depended on molecular subtype (Table). Uptake was lowest in HER2-HR+ and somewhat - but not significantly - higher in HER2+HR- disease. The highest SUVmax was found in HER2+HR+, followed by TN disease (both significantly higher than HER2-HR+). The interaction between HR and HER2 in relation to FDG uptake was significant (P=0.003). ANCOVA showed that the higher TN uptake could largely be explained by differences in grade, whereas SUVmax in HER2+HR+ disease remained significantly higher than in HER2-HR+ disease. Conclusion: This large series of advanced primary breast cancer showed FDG uptake to be comparably low in HER2-HR+ and HER2+HR- disease, but significantly higher in HER2+HR+ and TN disease. Tumor grade largely explained the higher FDG uptake in TN disease but not the results for HER2+HR+. FDG-PET may need evaluation at different settings taking into account uptake variation due to tumor biology. ![Figure][1] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4558. doi:1538-7445.AM2012-4558 [1]: pending:yes

Clinical/pathologic features and survival of patients with fibrolamellar-hepatocellular carcinoma (FLL-HCC): Data from the Fibrolamellar-Hepatocellular (FLL-HCC) Consortium.

4089 Background: FLL-HCC is rare and develops in young individuals of either gender in the absence of underlying liver disease. There are limited data on the demographics and outcome of FLL-HCC. METHODS Institutional review board-approved medical record review was undertaken for all FLL-HCC patients seen since 1986 at Memorial Sloan-Kettering Cancer Center, the University of California at San Francisco and Johns Hopkins University. Demographic, clinical/pathologic, and treatment data were gathered. Kaplan-Meier survival outcomes were compared using the log-rank test. RESULTS Ninety-eight patients with pathologically confirmed FLL-HCC were identified. Median age at diagnosis was 23 years (range 11-65). Race: 87 (89%) White, 2 (2%) Hispanic, 3 (3%) Asian, 4 (4%) Black, and 2 (2%) unknown. TNM stage was 18 (18%), 17 (17%), 10 (10%) and 43 (44%) for stage I, II, III and IV disease, respectively. Stage was unknown for 10 (10%) patients. Seventy-six (78%) patients underwent surgery, and 19 received peri-operative therapy: neoadjuvant 8 (42%), adjuvant 9 (47%) and 2 (11%) both. Median overall survival was 6.3 years. Univariate analyses of survival outcome based on different variables are shown in the table. CONCLUSIONS This is the largest reported series of patients with FLL-HCC. Patients with advanced, unresectable disease fare poorly, underscoring an urgent need for effective systemic therapies. The improved survival of males compared to females warrants further investigation. The FLL-HCC Consortium aims to promote awareness of this disease and to provide a platform for therapeutic development. This work was supported by the Fibrolamellar Foundation. [Table: see text].