Pathology of BRCA1- and BRCA2-associated Breast Cancers: Known and Less Known Connections.

INTRODUCTION: BRCA1/BRCA2 mutation carriers indefinitely comprise a distinct group of patients with breast cancer (BC), with their tumors displaying specific pathologic characteristics. Although these connections are known, they are not fully elucidated. We therefore sought to investigate the clinicopathologic characteristics and overall survival of Greek patients with BC carrying BRCA1/BRCA2 mutations. PATIENTS AND METHODS: Greek patients with BC diagnosed between 1999 and 2016, fulfilling the National Comprehensive Cancer Network criteria for genetic testing, were analyzed for BRCA1/BRCA2 mutations by Sanger sequencing or by a 94-gene panel. Medical records and pathology reports were retrospectively reviewed to retrieve patient and tumor baseline characteristics. Potential associations with mutation status were assessed using the Fisher exact, Pearson χ2, and Mann-Whitney tests. RESULTS: Of 2096 selected patients with BC, we identified 297 (14.2%) BRCA1 and 88 (4.2%) BRCA2 carriers. The mean age at BC diagnosis was 40 and 42.6 years, respectively (P = .02). Tumor histologic subtypes in BRCA1 and BRCA2 carriers were predominantly ductal (79%) followed by medullary (10%), and ductal (72%) followed by lobular (15%), respectively. A significantly higher percentage of BRCA2 tumors were human epidermal growth factor receptor 2-positive, compared with BRCA1 tumors (21.7% vs. 5.8%; P < .001). Second primary cancer diagnosis was more frequent in BRCA1 compared with BRCA2 mutation carriers (36.2% vs. 10.7%; P < .001), whereas there was no difference in 15-year overall survival (hazard ratio, 0.92; 95% confidence interval, 0.48-1.83; P = .804) between the 2 groups. CONCLUSIONS: These data confirm established observations in the pathology of BRCA-related tumors and provide further insight on the association of rare histologic entities with mutations in these genes, which can be clinically beneficial.

[Radiation therapy in thyroid cancer]. / Place de la radiothérapie externe dans les cancers de la thyroïde.

Anaplastic thyroid cancers represent 1-2% of all thyroid tumours and are of very poor prognosis even with multimodality treatment including external beam radiation therapy. Conversely, differentiated thyroid carcinomas (at least 80% of thyroid cancers) hamper good prognosis with surgery with or without radioiodine and there is hardly any room for external beam radiation therapy. Insular and medullar carcinomas have intermediary prognosis and are rarely irradiated. We aimed to update recommendations for external beam irradiation in these different clinical situations and put in light the benefits of new irradiations techniques. A search of the French and English literature was performed using the following keywords: thyroid carcinoma, anaplastic, chemoradiation, radiation therapy, surgery, histology and prognostic. Non-mutilating surgery (often limited to debulking) followed by systematic external beam radiation therapy is the standard of care in anaplastic thyroid cancers (hyperfractionated-accelerated radiation therapy with low-dose weekly doxorubicin with or without cisplatin if possible). Given anaplastic thyroid cancers' median survival of 10 months or less, neoadjuvant and adjuvant chemotherapy may also be discussed. Ten-year survival rates for patients with papillary, follicular and Hürthle-cell carcinomas are 93%, 85%, and 76%, respectively. Massive primary incompletely resected iodine-negative disease indicates external beam radiation therapy. Older age (45 or 60-year-old), poor-prognosis histological variants (including tall cell cancers) and insular cancers are increasingly reported as criteria for external beam radiation therapy. Massive extracapsular incompletely resected nodal medullary disease suggests external beam radiation therapy. Radiation therapy morbidity has been an important limitation. However, intensity modulated radiation therapy (IMRT) offers clear dosimetric advantages on tumour coverage and organ sparing, reducing late toxicities to less than 5%. The role of radiation therapy is evolving for anaplastic thyroid cancers using multimodal strategies and new chemotherapy molecules, and for differentiated cancers using minor criteria, such as histological variants, with IMRT becoming a standard of care.

Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer.

PURPOSE: Mutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC. PATIENTS AND METHODS: In this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily. RESULTS: Of 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21+ months, four patients had SD >or= 15 months, four patients had SD

Comorbidity in newly diagnosed thyroid cancer patients: a population-based study on prevalence and the impact on treatment and survival.

BACKGROUND: Comorbidity may be an important contributory factor to differences in the treatment and outcome of cancer, especially in older patients. It might also provide information on the aetiology of the cancer in cases of high or low frequency. The aim of this study was to describe the spectrum of comorbidity and the possible impact on treatment and survival in newly diagnosed thyroid cancer (TC). DESIGN: A population-based observational study. SETTING: The Eindhoven Cancer Registry, Comprehensive Cancer Centre South (IKZ), the Netherlands. METHODS: Demographic, histological and treatment data on all 417 TC patients diagnosed between 1 January 1993 and 31 December 2002 were collected and followed up till 2004. An adapted version of the list of Charlson was used for registration of clinically relevant concomitant disorders. The prevalence of comorbidity at diagnosis was analysed according to gender, age, histological type and therapy. Crude 6-month and 1- and 5-year survival rates were determined. A regression analysis was performed to identify independent variables related to survival. RESULTS: Information on comorbidity was available for 378 patients (91%). Comorbidity was present in 32% of the patients; 23% had one and 12% had two or more concomitant diseases. The prevalence of comorbidity increased with age. Hypertension was the most frequent comorbidity (18%), followed by 'other cancers' (7%), cardiovascular diseases (6%) and diabetes mellitus (6%). The prevalence of hypertension was twice as high as expected at all age groups. Six patients > 60 years had had tuberculosis. Initial surgical treatment was negatively related to the presence of concomitant diseases in patients < 70 years (P = 0.02), but not in patients > or = 70 years. Comorbidity was not independently associated with crude survival up to 5 years. CONCLUSIONS: A previous diagnosis of hypertension was associated with TC. The use of external radiation for diagnostic and therapeutic procedures for tuberculosis probably explains the high prevalence of former tuberculosis in elderly TC patients. Treatment choices appeared to be influenced by the presence of comorbidity. Comorbidity did not affect survival up to 5 years; a study with a longer period of follow-up is needed.

The therapeutic value of SST-A octreotide alone or with adjuvant treatment in patients with advanced medullary thyroid carcinoma and positive (111)In-octreotide scan.

Medullary thyroid carcinoma (MTC) as a neuroendocrine tumour arising from C cells of the thyroid gland secrets hormonal peptides; among them, calcitonine (CT) and carcino-embryonic antigen (CEA). These two peptides are used for the diagnosis and treatment response of MTC cases. In patients with advanced MTC, scintigraphy by [(111)In-DTPA-d-phe1]-octreotide is able to detect somatostatin receptors (SSTR) and thus identify regional lymph nodes and/or distal metastases. In this article, we have studied the use of [(111)In-DTPA-d-phe1]-octreotide in the treatment of patients with advanced MTC, and a positive octreotide scan. Twenty-two patients were studied, 16 with persistent MTC and six with relapsed MTC. All patients' tumours were detected by [(111)In-DTPA-d-phe1]-octreotide-scan to be SSTR positive. All patients were treated with the somatostatin analog (SST-A) octreotide, for 3-21 months. Nine patients were treated only with SST-A (Group A). The remaining 13 patients (Group B) received adjuvant treatment as follows: six patients received chemotherapy (Ch), five patients received both Ch and external radiotherapy (eRT) and two patients received only eRT. Results were as follows: Group B patients as compared to Group A patients had about the same objective and biological response. Patients of Group B had relatively better subjective response (less diarrheas and abdominal cramps) versus Group A patients, although this finding was not significant. Group B patients had a longer mean survival time after treatment as compared to Group A patients: 39 months (with a range of 4-72 months) versus 20 months (with a range of 3-60 months) respectively, (P<0.05). Also Group B patients had longer than Group A patients mean total survival time - measured from the start of the disease: 138 (18-270) versus 97 (13-235) months respectively (P<0.05). Based on the above findings, it is the opinion of the authors that patients with advanced MTC and SSTR tumor expression in vivo as indicated by [(111)In-DTPA-d-phe1]-octreotide scanning, when submitted to treatment with SST-A octreotide and adjuvant Ch and/or eRT treatment may have a better treatment response than if submitted to treatment with SST-A octreotide alone. More cases are being studied by us at the present.

Long-term survival rates in young patients with thyroid carcinoma.

BACKGROUND: Thyroid carcinoma in patients younger than 18 years is rare. It is associated with a greater risk of metastases. However, the prognosis for these patients is better when compared with that of adults. OBJECTIVE: To present the experience of a single institution in the treatment of patients with thyroid carcinoma during childhood and adolescence. PATIENTS AND METHODS: Thirty-eight patients, ranging in age from 4 to 18 years, were diagnosed as having thyroid carcinoma. Pathologic types of carcinoma included 29 papillary, 4 follicular, 1 Hürthle cell, and 4 medullary cases. RESULTS: Hypocalcemia was the main complication, being transitory in 9 patients (24%) and permanent in 6 patients (16%). Vocal cord palsy occurred in 2 patients (5%). Two patients (5%) had a surgical site infection. After a mean follow-up of 9.5 years (range, 1-40 years), 28 patients (74%) were alive and had no evidence of disease, 3 (8%) were alive and had recurrent disease, 4 (11%) died (2 of the disease and 2 of non-cancer-related causes), and 3 (8%) were lost to follow-up. The survival rates at 10 years for the patients with papillary, follicular, and medullary carcinoma were 93%, 100%, and 50%, respectively. CONCLUSIONS: Thyroid carcinoma in patients younger than 18 years has a good prognosis even in the presence of neck or distant metastasis. Total thyroidectomy, associated with adjuvant radioactive iodine therapy and thyroidal suppression or not, is effective in patients with a well-differentiated thyroid carcinoma.

A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns].

BACKGROUND: The National Cancer Data Base (NCDB) represents a national electronic registry system now capturing nearly 60% of incident cancers in the U. S. In combination with other Commission on Cancer programs, the NCDB offers a working example of voluntary, accurate, cost-effective "outcomes management" on a both a local and national scale. In addition, it is of particular value in capturing clinical information concerning rare cancers, such as those of the thyroid. METHODS: For the accession years 1985-1995, NCDB captured demographic, patterns-of-care, stage, treatment, and outcome information for a convenience sample of 53,856 thyroid carcinoma cases (1% of total NCDB cases). This article focuses on overall 10-year relative survival and American Joint Committee on Cancer (AJCC) (3rd/4th edition) stage-stratified 5-year relative survival for each histologic type of thyroid carcinoma. Care patterns also are discussed. RESULTS: The 10-year overall relative survival rates for U. S. patients with papillary, follicular, Hürthle cell, medullary, and undifferentiated/anaplastic carcinoma was 93%, 85%, 76%, 75%, and 14%, respectively. For papillary and follicular neoplasms, current AJCC staging failed to discriminate between patients with Stage I and II disease at 5 years. Total thyroidectomy +/- lymph node sampling/dissection represented the dominant method of surgical treatment rendered to patients with papillary and follicular neoplasms. Approximately 38% of such patients receive adjuvant iodine-131 ablation/therapy. At 5 years, variation in surgical treatment (i.e., lobectomy vs. more extensive surgery) failed to translate into compelling differences in survival for any subgroup with papillary or follicular carcinoma, but longer follow-up is required to evaluate this. NCDB data appeared to validate the AMES prognostic system, as applied to papillary cases. Younger age appeared to influence prognosis favorably for all thyroid neoplasms, including medullary and undifferentiated/anaplastic carcinoma. NCDB data also revealed that unusual patients diagnosed with undifferentiated/anaplastic carcinoma before age of 45 years have better survival. CONCLUSIONS: The NCDB system permits analysis of care patterns and survival for large numbers of contemporaneous U. S. patients with relatively rare neoplasms, such as thyroid carcinoma. In this context, it represents an unsurpassed clinical tool for analyzing care, evaluating prognostic models, generating new hypotheses, and overcoming the volume-related drawbacks inherent in the study of such neoplasms. [See editorial on pages 2434-6, this issue.]