Presumed mast cell choroidal infiltrate in aggressive systemic mastocytosis.

PURPOSE: To report a rare case of a unilateral choroidal mast cell infiltration in a patient with aggressive systemic mastocytosis (ASM). OBSERVATIONS: The patient is a man in his fifties with a diagnosis of ASM. He developed visual complaints in the right eye associated with an area of subretinal fluid on fundus examination. Visual acuity at presentation was 20/150 in the right eye and 20/25 in the left eye. After ophthalmic and radiologic imaging workup, the patient was diagnosed with presumed choroidal mast cell infiltrate. The index of suspicion was high due to the prior ASM diagnosis. External beam radiation and intravitreal injection treatments were offered but the patient declined. The patient was switched from interferon to a new targeted systemic therapy for ASM, midostaurin. Despite some mixed, temporary response in systemic symptoms/signs of ASM at four months, the choroidal lesion and subretinal fluid were stable with visual acuity at 20/125. CONCLUSION AND IMPORTANCE: Mast cell choroidal infiltration in ASM should be considered as part of the differential with acute/subacute vision changes. Diagnosis requires exclusion of other possibilities with ocular imaging and in this case, monitoring for development of other malignancies in which there were none. Midostaurin's ocular response was not on par with systemic response. Additional localized ocular therapies may be required.

Locoregional and Overall Recurrence After Neaodjuvant Endocrine Therapy Versus Chemotherapy in Postmenopausal Women With Estrogen Receptor+ HER2- Breast Cancer.

PURPOSE: We report clinical outcomes in patients treated with neoadjuvant endocrine therapy (NET) versus neoadjuvant cytotoxic chemotherapy (NCT) in a cohort of postmenopausal women with ER+, HER2- breast cancer. MATERIALS AND METHODS: We retrospectively reviewed 140 patients treated between May 1998 and September 2010 and collected patient, disease, and treatment characteristics, response to neoadjuvant therapy, and clinical outcome. RESULTS: The median age was 59.5 years. Stage group: stage I 2.2%, stage II 26.8%, stage III 71%, the median tumor size 6 cm (range, 1.5 to 19 cm). Fifty-seven (40.7%) received NET and 83 (59.3%) NCT. One patient (1.8%) in the NET group and 7 (8.4%) in the NCT group had a pathologic complete response (P=0.142). The median follow-up was 48.1 months. Five-year cumulative incidence of locoregional recurrence (LRR) among the entire cohort was 4.1% (95% confidence interval [CI]: 1.5, 8.9), and any recurrence 25.3% (95% CI: 17.6, 33.6). There was no difference in cumulative incidence of LRR or overall recurrence between NET and NCT. On multivariate analysis adjusting for receipt of chemotherapy, presenting stage, and positive lymph nodes, the use of adjuvant radiation therapy was associated with decreased risk of LRR (hazard ratio [HR]=0.24, P=0.035), and ypN2 status with higher risk of LRR (HR=4.91, P=0.032). When the same multivariate model was fitted for any recurrence outcome, only ypN2 status was a significant predictor of overall recurrence (HR=3.02, P=0.005). CONCLUSIONS: We have demonstrated equivalent locoregional and overall outcomes in patients receiving NET versus NCT in a cohort of postmenopausal women with locally advanced ER+HER2-tumors.

Characterizing Molecular Variants and Clinical Utilization of Next-generation Sequencing in Advanced Breast Cancer.

Women with advanced breast carcinomas have few therapeutic options. Recent advances in genomic profiling represent a new paradigm of cancer classification and treatment, but experience with genomic testing in a clinical setting remains limited. We retrospectively determined the genomic variants and correlate these with histology [histomorphologic subtype, nuclear grade, standard immunohistochemistry (IHC)] and clinical utilization (ordering, turnaround time, report review, and targeted therapy). Among 48 patients, 2 showed no genetic alterations, 11 (23%) showed variants of unclear significance only and 35 (73%) showed variant(s) affecting function (VaF) and/or variants of unclear significance. Overall, 119 variants were observed in 20 of 50 tested genes. Each patient had a unique molecular profile, with numerous (n=58) variants not previously reported in breast cancer. VaF detected in more than 2 patients included: TP53 (n=21), PIK3CA (n=20), and FGFR1 (n=3). VaF comprised 46 single nucleotide variants (79%), 7 amplifications (12%), 3 frameshifts (5%), 1 insertion (2%), and 1 deletion (2%). The tested samples had very high Ki67 index (average 57%±23%) and approximately half were hormone receptor and HER2 negative (25/46, 54%). Metastatic breast carcinomas showed a higher average VaF versus breast-localized tumors (1.3±0.99 vs. 0.18±0.60, P<0.05). Next-generation sequencing reports were promptly reported and reviewed (average 1 to 2 d) and 7 (∼25%) of potentially eligible patients received targeted therapy. Advanced breast cancers show unique landscapes of genetic variants. Most testing was done in late disease, often in metastatic and receptor-negative carcinomas. Next-generation sequencing results were promptly reported and reviewed, but the utilization of targeted therapies was limited.

Sensitive Detection of Mono- and Polyclonal ESR1 Mutations in Primary Tumors, Metastatic Lesions, and Cell-Free DNA of Breast Cancer Patients.

PURPOSE: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA). EXPERIMENTAL DESIGN: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n = 43), bone (n = 12) and brain metastases (n = 38), and cfDNA (n = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. RESULTS: ESR1 mutations were detected for D538G (n = 13), Y537S (n = 3), and Y537C (n = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3% to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n = 5), mutations were detected in both (n = 3) or in cfDNA only (n = 2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. CONCLUSIONS: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease. See related commentary by Gu and Fuqua, p. 1034.

Survival of patients with de-novo metastatic breast cancer: analysis of data from a large breast cancer-specific private practice, a university-based cancer center and review of the literature.

Approximately 6 % of patients with breast cancer are diagnosed with de-novo distant metastases. We set out to look at two cohorts of patients seen at breast cancer-specific practices, compare the results to other reports and larger databases, and see how advances in treatment have impacted overall survival (OS). The records from a large breast cancer oncology private practice and a second data set from the University of Miami/Sylvester Comprehensive Cancer Center (UM/SCCC) tumor database were, retrospectively, reviewed to identify patients with de-novo metastases. We included those patients identified to have metastatic disease within 3 months of diagnosis of a breast primary cancer. Patients diagnosed between 1996 and 2006 were chosen for our study population. The OS for the private practice was 41.0 months (46.0 for ER positive and 26.0 for ER negative) and 36.0 months for UM/SCCC (52 months for ER positive and 36 months for ER negative). ER negativity and CNS- or visceral-dominant disease were associated with a significantly worse prognosis within the private practice. Dominant site was associated with a significantly worse prognosis within the UM/SCCC database but with a trend also for ER negativity. Age and ethnicity did not contribute significantly to the survival of patients within either cohort. The median survival in both cohorts and most other reported series was larger than that seen in the surveillance, epidemiology, and end results program and the National Cancer Database. The median OS among patients with de-novo metastatic breast cancer treated within two breast-specific oncology practices was over 3 years, which appears better than larger, more inclusive databases and publications from earlier decades.

Defining the survival benchmark for breast cancer patients with systemic relapse.

BACKGROUND: Our original paper, published in 1992, reported a median overall survival after first relapse in breast cancer of 26 months. The current retrospective review concentrates more specifically on patients with first systemic relapse, recognizing that subsets of patients with local recurrence are potentially curable. METHODS: Records of 5,168 patients from a largely breast-cancer-specific oncology practice were reviewed to identify breast cancer patients with their first relapse between 1996 and 2006 after primary treatment. There were 189 patients diagnosed with metastatic disease within 2 months of being seen by our therapeutic team and 101 patients diagnosed with metastatic disease greater than 2 months. The patients were divided in order to account for lead-time bias than could potentially confound the analysis of the latter 101 patients. RESULTS: Median survival for our primary study population of 189 patients was 33 months. As expected, the median survival from first systemic relapse (MSFSR) for the 101 patients excluded because of the potential for lead-time bias was better at 46 months. Factors influencing prognosis included estrogen receptor (ER) status, disease-free interval (DFI), and dominant site of metastasis. Compared with our original series, even with elimination of local-regional recurrences in our present series, the median survival from first relapse has improved by 7 months over the past two decades. CONCLUSION: The new benchmark for MSFSR approaches 3 years.

A retrospective study evaluating a fixed low dose capecitabine monotherapy in women with HER-2 negative metastatic breast cancer.

To determine if a low fixed dosing strategy of capecitabine would produce comparable clinical activity with less adverse toxicities compared to published data with higher doses in the setting of metastatic breast cancer (mBC). We retrospectively analyzed patients treated with a low fixed dose of capecitabine (CAPE-L) at 1,000 mg twice daily for 14 days every 21 days. Outcomes included clinical benefit rate (CBR), overall response rates (ORR), time to progression (TTP), and overall survival (OS). A historical comparison group of mBC patients treated on 12 prior trials at the package-insert dose of capecitabine (n = 1,949) was utilized. Eighty-six patients were analyzed in our cohort. Positive hormone receptor status (79.1 vs. 50.6 %), and capecitabine as first-line chemotherapy (44.2 vs. 16.5 %) were more frequent in our cohort relative to the historical comparison. The median starting dose in our cohort was 633.5 mg/m(2). The CBR was similar between the CAPE-L and the standard dose cohorts (55.8 vs. 49.5 %), as was ORR (24.3 vs. 24 %), and median TTP (7 mo, 95 % CI 5.5-8.5 vs. 5.1 mo, 95 % CI 4.5-5.7). Median OS was longer in our cohort (24 mo, 95 % CI 16.8-31.2) than the historic standard dose cohort (12.1 mo, 95 % CI 9.6-14.4), a difference that was likely explained by the higher proportion of patients in the CAPE-L cohort who received capecitabine as first-line chemotherapy and who had hormone receptor positive disease. As expected, adverse events were less frequent with CAPE-L. We found that CAPE-L, which translates into a dose of 600-650 mg/m(2), appeared to have good clinical efficacy and acceptable toxicity.

The development of two different malignancies in a patient with large congenital melanocytic nevus.

Patients with large congenital melanocytic nevus (LCMN) have a high risk of developing malignant melanoma (MM) and other malignancies. We report a case of a mesenchymal malignancy that best fit the diagnosis of a malignant peripheral nerve sheath tumor and subsequent development of a MM developing from a LCMN. There are no previous reports of a second primary malignant neoplasm arising from a LCMN.