Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir ± Ribavirin for HCV in Brazilian Adults with Advanced Fibrosis.

INTRODUCTION AND AIM: Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an openlabel multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection. MATERIAL AND METHODS: All patients received coformulated OBV/PTV/r daily + DSV twice daily (3-DAA). GT1a-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/RBV nonresponders with cirrhosis who were treated for 24 weeks. GT1b-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA < 15 IU/mL) at post-treatment Week 12 (SVR12). RESULTS: The study enrolled 222 patients, 214 achieved an SVR12 (96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR12 was achieved in 111/ 112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event. DISCUSSION: The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).

Correlation between sonographic findings and clinicopathologic and biologic features of pure ductal carcinoma in situ in 691 patients.

OBJECTIVE: The objective of our study was to compare the sonographic features of pure ductal carcinoma in situ (DCIS) lesions with the initial clinical presentation and histopathologic findings. MATERIALS AND METHODS: The images and records of 691 patients with pure DCIS who underwent preoperative mammography and whole-breast sonography as part of staging workup in a single institution from January 1, 1996, through July 31, 2009, were reviewed. The BI-RADS sonography lexicon was used when reviewing the sonographic studies. Histopathologic features recorded included estrogen receptor (ER) status, nuclear grade, and presence or absence of comedonecrosis. Statistical comparisons were made using the Student t test, chi-square test, Fisher exact test, Kruskal-Wallis or Wilcoxon rank sum test, multiple logistic regression analysis, and Pearson correlation coefficient. RESULTS: A total of 304 (44%) tumors were visible on mammography and sonography; 315 (46%), on mammography only; 58 (8%), on sonography only; and 14 (2%), on neither mammography nor sonography. The most common sonographic appearance of DCIS was an irregular hypoechoic mass with indistinct margins and normal posterior features that was indistinguishable from invasive carcinoma. Patients with symptomatic high-nuclear-grade DCIS, dense breasts, and comedonecrosis were younger and had larger tumors on sonography than asymptomatic women with nondense breasts and low-nuclear-grade and noncomedo DCIS. Women with ER-negative DCIS were older and had larger tumors on sonography than women with ER-positive DCIS. ER-negative tumors were more frequently visible on sonography than ER-positive tumors (p=0.007). High-grade DCIS (p<0.0001) and comedo DCIS (p<0.0001) presented more frequently as microcalcifications, architectural distortion, and ductal changes on sonography than low-grade DCIS or noncomedo DCIS. CONCLUSION: Of the 691 pure DCIS lesions, 362 (52%) were visible on sonography and presented most commonly as a mass. Lesion visibility of DCIS on sonography was not related to nuclear grade or the presence of comedonecrosis.

Incidence and consequence of close margins in patients with ductal carcinoma-in situ treated with mastectomy: is further therapy warranted?

BACKGROUND: The impact of close margins in patients with ductal carcinoma-in situ (DCIS) treated with mastectomy is unclear; however, this finding may lead to a recommendation for postmastectomy radiotherapy (PMRT). We sought to determine the incidence and consequences of close margins in patients with DCIS treated with mastectomy. METHODS: The records of 810 patients with DCIS treated with mastectomy from 1996 through 2009 were reviewed. Clinical and pathologic factors were analyzed with respect to final margin status. Median follow-up was 6.3 years. RESULTS: Overall, 94 patients (11.7 %) had close margins (positive, n = 5; negative but ≤1 mm, n = 54; 1.1-2.9 mm, n = 35). Independent risk factors for close margins included multicentricity, pathologic lesion size ≥1.5 cm, and necrosis, but not age, use of skin-sparing mastectomy, or immediate reconstruction (p > 0.05). Seven patients received PMRT, and none had a locoregional recurrence (LRR). Among the remaining 803 patients, the 10-year LRR rate was 1 % (5.0 % for margins ≤1 mm, 3.6 % for margins 1.1-2.9 mm, and 0.7 % for margins ≥3 mm [p < 0.001]). The 10-year rate of contralateral breast cancer was 6.4 %. On multivariate analysis, close margins was the only independent predictor of LRR (p = 0.005). CONCLUSIONS: Close margins occur in a minority of patients undergoing mastectomy for DCIS and is the only independent risk factor for LRR. As the LRR rate in patients with close margins is low and less than the rate of contralateral breast cancer, PMRT is not warranted except for patients with multiple close/positive margins that cannot be surgically excised.

Clinical course of breast cancer patients with isolated sternal and full-thickness chest wall recurrences treated with and without radical surgery.

BACKGROUND: The role and outcome of radical surgery in contemporary multidisciplinary management of breast cancer patients presenting with isolated sternal or fullthickness chest wall (SCW) recurrence are undefined compared with patients treated without surgery. METHODS: Detailed analyses of all patients with isolated SCW recurrence treated from 1992 to 2011 at a large cancer institution were performed. Univariate and multivariate comparisons of clinicopathologic and treatment characteristics were analyzed. Overall and progression-free survival were compared using the Kaplan­Meier method. RESULTS: Seventy-six patients were identified, 44 treated surgically and 32 nonsurgically. Overall survival at 5 years was not statistically different between patients who underwent surgery and those who did not (30.6 and 49.6 %, respectively; P = 0.52) although patients selected for surgery presented with more advanced and biologically aggressive disease. Surgically treated patients were more likely to have triple-negative breast cancer at recurrence (52 vs. 17 %; P = 0.006). Among surgical patients, 95 % received preoperative systemic therapy. Clinical response with systemic therapy was significantly different, with surgically treated patients more likely to have responsive or stable disease (54 vs. 25 %, P = 0.04). Complications related to radical surgical resection occurred in 25 % of patients. For hormone receptor­positive recurrence, 5-year progression-free survival was significantly higher among surgical patients (46.3 vs. 14.5 %; P = 0.01). CONCLUSIONS: Among patients with isolated SCW recurrence, hormone receptor-positive recurrence is associated with improved survival. Systemic therapy should be the initial treatment, and clinical response can be used to help select patients who may benefit from radical resection.

Clinicopathologic, mammographic, and sonographic features in 1,187 patients with pure ductal carcinoma in situ of the breast by estrogen receptor status.

The clinicopathologic, mammographic, and sonographic findings in patients with pure ductal carcinoma in situ (DCIS) were assessed by estrogen receptor (ER) expression. After institutional review board approval, patients with pure DCIS evaluated from January 1996 to July 2009 with known ER status and available imaging were identified. Images were reviewed as per the ACR BI-RADS(®) lexicon (4th edition). Clinical, pathologic, and imaging characteristics were analyzed by ER status using t test, Chi square test, and Fisher's exact test. Of 1,219 patients with pure DCIS and known ER status identified, 1,187 with complete data were included. Mammography was performed in all 1,187 patients and sonography in 519 (44 %). There were 972 (82 %) patients with ER-positive and 215 (18 %) with ER-negative disease. ER-negative DCIS was more likely to be high grade (93 vs 44 %, p < 0.0001), associated with comedonecrosis (64 vs 29 %, p < 0.0001), and multifocal (23 vs 15 %, p = 0.009). On sonography, ER-negative DCIS was more likely to be visible (61 vs 46 %, p = 0.004), larger (mean size, 2.3 vs 1.6 cm, p = 0.006), and show posterior shadowing (53 vs 28 %, p = 0.006). Mastectomy was more frequently performed for ER-negative DCIS (47 vs 37 %, p = 0.008). Palpable DCIS was visible on sonography in 55 % of cases and mammography in 81 %. Compared with ER-positive palpable DCIS, ER-negative palpable DCIS was larger and more likely to be visible on sonography. Compared with ER-positive noncalcified DCIS, ER-negative noncalcified DCIS was less likely to be visible on mammography. ER-positive and ER-negative pure DCIS have different clinicopathologic and imaging characteristics. ER-negative DCIS is associated with worse prognostic factors than ER-positive DCIS. On sonography, ER-negative DCIS is more frequently visible than ER-positive DCIS, tends to be larger, and more frequently demonstrates posterior shadowing.

Impact of race and ethnicity on features and outcome of ductal carcinoma in situ of the breast.

BACKGROUND: The impact of race and ethnicity on the biologic features and outcome variables of women who are diagnosed with preinvasive breast cancer-ductal carcinoma in situ (DCIS)-has not been addressed widely in the published literature. METHODS: Patient demographic, clinical, and pathologic features and outcome variables were analyzed with respect to the patient's initial self-reported race/ethnicity among women who received treatment for a diagnosis of pure DCIS from 1996 to 2009. RESULTS: Of 1902 patients, 1411 were white (74.2%), 214 were African American (11.3%), 175 were Hispanic (9.1%), and 102 were Asian/Pacific Islander (5.4%). The majority of patients were between ages 41 and 70 years (83%). Patients of Hispanic and Asian/Pacific Islander descent were significantly younger than white and African American patients (P < .001). DCIS size and grade, the presence of necrosis, and the frequency of breast-conserving surgery did not differ significantly between groups. African American patients aged >70 years and Hispanic patients aged <50 years were significantly more likely to have estrogen receptor-positive DCIS than patients of other races in the same age categories (P < .001). Adjuvant radiotherapy and tamoxifen were received significantly less often by white women (P < .001). At a median follow-up of 4.8 years (range, 1-14 years), recurrence rates and the development of contralateral breast cancer did not differ significantly among racial/ethnic groups when stratified by treatments received. CONCLUSIONS: There was variation in age at presentation, biologic features, and treatment of DCIS among the different ethnic groups. Additional studies with larger numbers of ethnic minority patients are needed to confirm whether the consistent application of evidence-based treatment practices presents an opportunity for reducing disparities in patients with DCIS.

Biology, treatment, and outcome in very young and older women with DCIS.

BACKGROUND: This study examines a modern cohort of women with ductal carcinoma-in-situ (DCIS) in order to identify potential differences in clinical presentation, treatments, and outcome based on age. METHODS: From 1996 to 2009, a total of 2037 patients with pure DCIS were treated. Clinical presentation, pathologic factors, type of surgery and adjuvant therapy, and local recurrence rates among age groups were compared and analyzed. Median follow-up was 5.2 years. RESULTS: There were 132 patients (6.5 %) aged <40, 1,690 (83 %) aged 40-70, and 215 (10.5 %) aged >70. Younger patients (<40) were significantly more likely to have a family history of breast cancer, present with clinical symptoms, undergo mastectomy with immediate reconstruction, and have a contralateral prophylactic mastectomy (P < 0.05). Older patients (>70) were significantly less likely to use adjuvant radiotherapy and tamoxifen (P < 0.05). No significant differences were found in DCIS size, estrogen receptor status, necrosis, or contralateral breast cancer based on age. Among women <40, 29.3 % had evidence of multicentric disease versus 17.7 and 13.3 % in the women aged 40-70 and those >70, respectively (P = 0.004). On multivariate analysis, younger age (<40), larger-size DCIS (≥1.5 cm), and no use of radiotherapy were significant independent predictors of locoregional recurrence. The 5 year rates of local recurrence were 10.1 % in women <40 compared with 3.2 % in older women (P = 0.005). CONCLUSIONS: Younger patients with DCIS more often have multicentric disease, present with clinical findings, and opt for or require mastectomy with immediate reconstruction. Conservative surgery is only appropriate for younger patients if adjuvant radiotherapy is delivered.

Biologic features and prognosis of ductal carcinoma in situ are not adversely impacted by initial large body mass.

Obesity is associated with adverse biologic features and poor outcome in patients with invasive breast cancer, yet this relationship has not been evaluated in patients with ductal carcinoma in situ (DCIS). From 1996 to 2009, body mass index (BMI) was recorded at initial diagnosis for 1,885 patients with DCIS treated at our institution. Patients were categorized as obese (BMI ≥ 30 kg/m(2)), overweight (BMI 25 to <30 kg/m(2)), or of normal weight or underweight (BMI < 25 kg/m(2)). Logistic regression was used to examine associations between BMI and patient, clinical, and pathologic features and treatment. Local-regional recurrence was calculated using the Kaplan-Meier method. All statistical tests were two-sided. Of the 1,885 patients, 514 (27.7%) were obese, 510 (27.5%) were overweight, and 831 (44.8%) were normal/underweight. In multivariate analysis, overweight and obese patients were significantly more likely to be African American (odds ratio [OR], 3.93; 95% confidence interval [CI], 2.66-5.80) or Hispanic (OR, 1.44; CI, 1.02-2.04), be postmenopausal (OR, 1.63; CI, 1.28-2.07), have diabetes (OR, 4.60; CI, 2.60-8.12), have estrogen-receptor-positive DCIS (OR, 1.39; CI, 1.00-192), and present with a radiologic abnormality rather than clinical symptoms (OR, 1.35; CI, 1.01-1.80). At a median follow-up time of 4.96 years (range, 1.0-14.34 years), no significant differences in local recurrence rates were detected based on patients' initial BMI category. Furthermore, there was no significant difference in risk of recurrence between diabetic patients receiving metformin or not. In conclusion, higher BMI is not associated with adverse biologic features or prognosis in patients with DCIS.

Biological Markers in DCIS and Risk of Breast Recurrence: A Systematic Review.

Understanding of the biology and clinical behavior of ductal carcinoma in situ (DCIS) is currently inadequate. The aim of this comprehensive review was to identify important molecular biological markers associated with DCIS and candidate markers associated with increased risk of ipsilateral recurrence after diagnosis of DCIS. A comprehensive systematic review was performed to identify studies published in the past 10 years that investigated biological markers in DCIS. To be included in this review, studies that investigated the rate of biological expression of markers had to report on at least 30 patients; studies that analyzed the recurrence risk associated with biomarker expression had to report on at least 50 patients. There were 6,252 patients altogether in our review. Biological markers evaluated included steroid receptors, proliferation markers, cell cycle regulation and apoptotic markers, angiogenesis-related proteins, epidermal growth factor receptor family receptors, extracellular matrix-related proteins, and COX-2. Although the studies in this review provide valuable preliminary information regarding the expression and prognostic significance of biomarkers in DCIS, common limitations of published studies (case-series, cohort, and case-control studies) were that they were limited to small patient cohorts in which the extent of surgery and use of radiotherapy or endocrine therapy varied from patient to patient, and variable methods of determining biomarker expression. These constraints made it difficult to interpret the absolute effect of expression of various biomarkers on risk of local recurrence. No prospective validation studies were identified. As the study of biomarkers are in their relative infancy in DCIS compared with invasive breast cancer, key significant prognostic and predictive markers associated with invasive breast cancer have not been adequately studied in DCIS. There is a critical need for prospective analyses of novel and other known breast cancer molecular markers in large cohorts of patient with DCIS to differentiate indolent from aggressive DCIS and better tailor the need and extent of current therapies.

Ductal carcinoma-in-situ of the breast with subsequent distant metastasis and death.

BACKGROUND: The rare patient diagnosed with pure ductal carcinoma-in-situ (DCIS) develops distant breast cancer metastases (DM). We sought to identify clinical and pathologic predictors of DM. METHODS: The clinical and pathologic characteristics of patients with DM after a diagnosis of pure DCIS from 1996 to 2009 were analyzed. RESULTS: Twenty five patients with DM after an initial diagnosis of DCIS were identified; 3 were treated at our institution and 22 were originally treated elsewhere. The rate of DM was 0.14% among 2,123 patients originally treated at our institution. Among all patients with DM, 73.7% had DCIS with necrosis, and 62% had DCIS that did not express estrogen receptor. Twenty-four percent of patients with DM were African American, compared to 11.5% of the total study population. The median time from DCIS to DM was 4.5 years. Sixteen patients (66%) had a preceding or simultaneous invasive locoregional recurrence (LRR); nine (34%) did not. At last follow-up, 14 patients (56%) had died of disease; median time to death was 2.4 years. No dominant variables could be identified in patients who developed DM with or without a LRR. CONCLUSIONS: DM after a diagnosis of pure DCIS is rare. Although most patients with DM have a preceding invasive LRR, some present with subsequent DM alone. Further study is required to identify clinical and pathologic predictors of this more rapid disease progression.