Seema A. Khan

A meta-analysis of human acellular dermis and submuscular tissue expander breast reconstruction

Background: Human acellular dermal matrix has become an increasingly used adjunct to traditional submuscular tissue expander/implant breast reconstruction, but there is no strong consensus regarding complication outcomes. This study stratified outcomes based on a meta-analysis of complications. Methods: A query of the MEDLINE database for articles on human acellular dermal matrix and submuscular tissue expander breast reconstruction yielded 901 citations. Two levels of screening identified 48 relevant studies. The DerSimonian and Laird random-effects model was used to perform the meta-analysis. Risk ratios and pooled complication rates were calculated for each outcome of interest. Results: Nineteen studies reporting human acellular dermal matrix (n = 2037) and 35 reporting submuscular outcomes (n = 12,847) were used to estimate complication rates. Rates were generally higher in acellular dermis patients: total complications, 15.4 versus 14.0 percent; seroma, 4.8 versus 3.5 percent; infection, 5.3 versus 4.7 percent; and flap necrosis, 6.9 versus 4.9 percent. Six studies reporting both acellular dermis and submuscular outcomes were used to estimate relative risks. There was an increased risk of total complications (relative risk, 2.05; 95 percent CI, 1.55 to 2.70), seroma (relative risk, 2.73; 95 percent CI, 1.67 to 4.46), infection (relative risk, 2.47; 95 percent CI, 1.71 to 3.57), and reconstructive failure (relative risk, 2.80; 95 percent CI, 1.76 to 4.45) in acellular dermis patients. Conclusions: The meta-analysis suggests that the use of human acellular dermal matrix increases complication rates vis-à-vis submuscular expander/implant reconstruction. This must be weighed against its reported advantages in enhancing cosmesis and ameliorating contracture. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Initial Surgery and Survival in Stage IV Breast Cancer in the United States, 1988-2011.

IMPORTANCEnManagement of the primary tumor site in patients with metastatic breast cancer remains controversial.nnnOBJECTIVEnTo evaluate the patterns of receipt of initial breast surgery for female patients with stage IV breast cancer in the United States, with particular attention to women who survived at least 10 years.nnnDESIGN, SETTING, AND PARTICIPANTSnA retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) program. Female patients diagnosed as having stage IV breast cancer between 1988 and 2011 and who did not receive radiation therapy as part of the first course of treatment were included (Nu2009=u200921u202f372). Kaplan-Meier estimates of median survival and descriptive statistics were used to compare patient and tumor characteristics by receipt of breast surgery at diagnosis. A Royston-Parmar survival model and logistic regression analysis assessed demographic and clinical factors associated with survival and prolonged survival (of at least 10 years).nnnMAIN OUTCOMES AND MEASURESnDifferences in survival, particularly survival of at least 10 years, by receipt of initial surgery to the primary tumor.nnnRESULTSnAmong the 21u202f372 patients, the median survival increased from 20 months (1988-1991) to 26 months (2007-2011). During this time, the rate of surgery declined (odds ratio [OR], 0.16; 95% CI, 0.12-0.21). Even so, receipt of surgery was associated with improved survival in multivariate analysis, which controlled for patient and clinical characteristics, along with time period (hazard ratio, 0.60; 95% CI, 0.57-0.63). For women diagnosed as having cancer before 2002 (nu2009=u20097504), survival of at least 10 years was seen in 9.6% (nu2009=u2009353) and 2.9% (nu2009=u2009107) of those who did and did not receive surgery, respectively (OR, 3.61; 95% CI, 2.89-4.50). In multivariate analysis, survival of at least 10 years was associated with receipt of surgery (odds ratio, 2.80; 95% CI, 2.08-3.77), hormone receptor-positive disease (OR, 1.76; 95% CI, 1.25-2.48), older age (OR, 0.41; 95% CI, 0.32-0.54), larger tumor size (OR, 0.37; 95% CI, 0.27-0.51), marital status of being separated at the time of diagnosis (OR, 0.67; 95% CI, 0.51-0.88), and more recent year of diagnosis (OR, 1.43; 95% CI, 1.02-1.99).nnnCONCLUSIONS AND RELEVANCEnSurvival in stage IV breast cancer has improved and is increasingly of prolonged duration, particularly for some women undergoing initial breast surgery. As systemic therapy advances provide better control of distant disease in stage IV breast cancer, and as women present with lower distant disease burdens, these findings on initial surgery to the primary tumor may be of importance.

A Randomized Phase II Presurgical Trial of Transdermal 4-Hydroxytamoxifen Gel versus Oral Tamoxifen in Women with Ductal Carcinoma In Situ of the Breast

Purpose: Local transdermal therapy to the breast may achieve effective target-organ drug delivery, while diminishing systemic effects. We conducted a randomized, double-blind, placebo-controlled phase II trial comparing transdermal 4-hydroxytamoxifen gel (4-OHT) to oral tamoxifen (oral-T) in women with ductal carcinoma in situ (DCIS). Methods: Twenty-seven pre- and postmenopausal women were randomized to 4-OHT (4 mg/day) or oral-T (20 mg/day) for 6 to 10 weeks before surgery. Plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites were determined by liquid chromatography/tandem mass spectrometry. The primary endpoint was Ki67 labeling in DCIS lesions, measured by immunohistochemistry. In plasma, insulin-like growth factor-1 (IGFI), sex hormone–binding globulin (SHBG), and coagulation protein concentrations were determined. Results: Posttherapy Ki67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (P ≤ 0.03 in both, between-group P = 0. 99). Mean plasma 4-OHT was 0.2 and 1.1 ng/mL in 4-OHT and oral groups, respectively (P = 0.0003), whereas mean breast adipose tissue concentrations of 4-OHT were 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (P = 0.88). There were significant increases in plasma SHBG, factor VIII, and von Willebrand factor and a significant decrease in plasma IGFI with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups. Conclusions: The antiproliferative effect of 4-OHT gel applied to breast skin was similar to that of oral-T, but effects on endocrine and coagulation parameters were reduced. These findings support the further evaluation of local transdermal therapy for DCIS and breast cancer prevention. Clin Cancer Res; 20(14); 3672–82. ©2014 AACR.

Impact of Guideline Changes on Use or Omission of Radiation in the Elderly with Early Breast Cancer: Practice Patterns at National Comprehensive Cancer Network Institutions

BACKGROUNDnBreast radiation therapy (RT) is a care standard after breast-conservation surgery that improves local control and survival in women. In 2004, a phase III trial demonstrated radiation after breast-conservation surgery provided no survival and limited local control benefit to women aged 70 years and older with stage I, estrogen receptor-positive cancers who receive endocrine therapy. This led to breast-conservation surgery and endocrine therapy alone being incorporated as a category I option in the National Comprehensive Cancer Network (NCCN) Guidelines for older women in 2004. We examined factors associated with change in radiation use in elderly patients at 13 NCCN centers.nnnSTUDY DESIGNnWe identified women treated at NCCN centers meeting age and stage criteria during 2000 to 2009. Factors considered a priori potentially associated with RT use were evaluated in univariate and multivariable models, including year of diagnosis, tumor and patient characteristics, axillary surgery, and treating institution. Date of diagnosis was classified as 2000 to 2004 vs 2005 to 2009, reflecting when guidelines changed.nnnRESULTSnAmong 1,292 eligible cases, 78% received RT. In multivariable analysis, diagnosis after 2004 (p = 0.0003), older age (p < 0.0001), higher comorbidity score (p = 0.0006), smaller tumors (p = 0.0146), and omission of axillary surgery (p < 0.0001) predicted RT omission. Ninety-four percent of women aged 70 to 74 years received RT in 2000, compared with 88% in 2009. For the same times and age 80 years and older, RT use was 80% vs 41%. Finally, RT use was associated with treating institution (p < 0.0001).nnnCONCLUSIONSnAfter guideline changes for RT use in older women, NCCN centers demonstrated wide variation in implementing change. This suggests other factors are also influencing guideline uptake.

Factors Associated with the Development of Chronic Pain after Surgery for Breast Cancer: A Prospective Cohort from a Tertiary Center in the United States

Chronic pain has been shown to affect up to 60% of patients undergoing surgery for breast cancer. Besides younger age, other risk factors for the development of chronic pain have not been consistent in previous studies. The objective of the current investigation was to detect the prevalence and risk factors for the development of chronic pain after breast cancer surgery by examining a patient population from a tertiary cancer center in the United States. The study was a prospective observational cohort study. Subjects were evaluated at least 6 months after the surgical procedure. Subjects responded to the modified short form Brief pain inventory and the short form McGill pain questionnaire to identify and characterize pain. Demographic, surgery, cancer treatment, and perioperative characteristics were recorded. Propensity matching regression analysis were used to examine risk factors associated with the development of chronic pain. 300 patients were included in the study. 110 reported the presence of chronic pain. Subjects with chronic pain reported median (interquartile range [IQR]) rating of worst pain in the last 24 hours of 4 (2–5) and a median (IQR) rating on average pain in the last 24 hours of 3 (1–4) on a 0–10 numeric rating scale. Independent risk factors associated with the development of chronic pain were age, OR (95% CI) of 0.95 (0.93–0.98) and axillary lymph node dissection, 7.7 (4.3–13.9) but not radiation therapy, 1.05(0.56–1.95). After propensity matching for confounding covariates, radiation was still not associated with the development of chronic pain. Chronic pain after mastectomy continues to have a high prevalence in breast cancer patients. Younger age and axillary lymph node dissection but not radiation therapy are risk factors for the development of chronic pain. Preventive strategies to minimize the development of chronic pain are highly desirable.

Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579).

AbstractnThe purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21xa0days, and eribulin 1.4xa0mg/m2 day 1 and day 8 every 21xa0days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD scorexa0+xa0BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3xa0%) patients enrolled in the study achieved pCR. 24 (80.0xa0%) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score (Pxa0=xa00.0024) and HR deficiency status (Pxa0=xa00.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR (Pxa0=xa00.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D (Pxa0=xa00.020), nuclear CDK4 (Pxa0=xa00.0030), and nuclear Smad3 (Pxa0=xa00.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population.n

Non-mass-associated intraductal papillomas: is excision necessary? ☆,☆☆

Intraductal papillomas (IDPs) of the breast can be associated with a variety of clinical symptoms and radiologic findings. Surgical excision is often recommended based on the possibility of an associated high-grade lesion. Although the rate of upgrades has been extensively evaluated for IDPs, many studies are hindered by broad inclusion criteria, a lack of pathologic-radiologic concordance, and no standard definition of what constitutes an upgrade. In the current study, we evaluate the risk of upgrade for a specific subset of IDPs: non-mass-associated IDPs. We identified all breast needle core biopsies with a diagnosis of IDP between 2003 and 2010. Patients with associated masses, architectural distortion, or ipsilateral breast cancer were excluded. All needle core biopsy slides and relevant imaging studies were reviewed to ensure pathologic-radiologic concordance. Excision pathology was also reviewed; an upgrade was defined as the presence of ductal carcinoma in situ or invasive carcinoma in the excision. Seventy-nine IDPs that met inclusion criteria were identified and were further divided into 3 histologic categories: micropapilloma, fragmented IDP, and atypical IDP. Micropapillomas and fragmented IDPs had no upgrades (0/37). In patients who did not undergo excision, none subsequently developed ipsilateral breast cancer (follow-up, 50-61 months). This is in contrast to atypical IDPs that had a 33% upgrade rate. One patient with an unexcised atypical IDP developed ipsilateral breast cancer within 2 years. Our data suggest that conservative follow-up is reasonable for non-mass-associated IDPs without atypia regardless of microscopic size, provided that careful pathologic-radiologic correlation is achieved.

A New Method for Predicting Patient Survivorship Using Efficient Bayesian Network Learning

The purpose of this investigation is to develop and evaluate a new Bayesian network (BN)-based patient survivorship prediction method. The central hypothesis is that the method predicts patient survivorship well, while having the capability to handle high-dimensional data and be incorporated into a clinical decision support system (CDSS). We have developed EBMC_Survivorship (EBMC_S), which predicts survivorship for each year individually. EBMC_S is based on the EBMC BN algorithm, which has been shown to handle high-dimensional data. BNs have excellent architecture for decision support systems. In this study, we evaluate EBMC_S using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset, which concerns breast tumors. A 5-fold cross-validation study indicates that EMBC_S performs better than the Cox proportional hazard model and is comparable to the random survival forest method. We show that EBMC_S provides additional information such as sensitivity analyses, which covariates predict each year, and yearly areas under the ROC curve (AUROCs). We conclude that our investigation supports the central hypothesis.

De novo Stage IV breast cancer: Breast conserving resection of the primary tumor?

Multiple retrospective reviews completed over the past decade suggest a survival advantage with resection of the intact primary tumor in women with metastatic breast cancer. However, these reviews are not without bias, and recently completed randomized trials do not support a significant survival benefit, although local control benefits may exist. Completion of ongoing trials is needed to reach a definitive conclusion regarding the merit of primary tumor resection for local control and survival. J. Surg. Oncol. 2014 110:51–57.

Local transdermal therapy to the breast for breast cancer prevention and DCIS therapy: preclinical and clinical evaluation.

AbstractPurposeWomen at high risk of breast cancer and those with carcinoma in situ need non-toxic, well-tolerated preventive interventions. One promising approach is drug delivery through the breast skin (local transdermal therapy, LTT). Our goal was to test novel drugs for LTT, to establish that LTT is applicable to non-steroidal drugs.MethodsAthymic nude rats were treated with oral tamoxifen, transdermal 4-hydroxytamoxifen (4-OHT) or endoxifen gel applied daily to the axillary mammary gland for 6xa0weeks (Study 1). Study 2 was identical to Study 1, testing transdermal telapristone acetate (telapristone) gel versus subcutaneous implant. At euthanasia, mammary glands and blood were collected. In Study 3, consenting women requiring mastectomy were randomized to diclofenac patch applied to the abdomen or the breast for 3xa0days preoperatively. At surgery, eight tissue samples per breast were collected from predetermined locations, along with venous blood. Drug concentrations were measured using liquid chromatography–tandem mass spectroscopy.nResultsMammary tissue concentrations of 4-OHT, endoxifen, and telapristone were significantly higher in the axillary glands of the gel-treated animals, compared to inguinal glands or to systemically treated animals. Plasma concentrations were similar in gel and systemically treated animals. The clinical trial showed significantly higher mammary concentrations when diclofenac was applied to the breast skin versus the abdominal skin, but concentrations were variable.ConclusionsThese results demonstrate that lipophilic drugs can be developed for LTT; although the nude rat is suitable for testing drug permeability, delivery is systemic. In human, however, transdermal application to the breast skin provides local delivery.