Prediction of Oncotype DX and TAILORx risk categories using histopathological and immunohistochemical markers by classification and regression tree (CART) analysis

Oncotype DX is an RT-PCR assay used to predict which patients with ER-positive node-negative (NN) disease will benefit from chemotherapy. Each patient is stratified into a risk category based on a recurrence score (RS) and the TAILORx trial is determining the benefit of chemotherapy for patients with mid-range RSs.We tested if Oncotype DX and TAILORx risk categories could be predicted by standard pathological features and protein markers corresponding to 10 genes in the assay (ER, PR, Ki67, HER2, BCL2, CD68, Aurora A kinase, survivin, cyclin B1 and BAG1) on 52 patients who enrolled on TAILORx. Immunohistochemistry for the protein markers was performed on whole tissue sections.Classification and regression tree (CART) analysis correctly classified 69% of cases into Oncotype DX risk categories based on the expression of PR, survivin and nuclear pleomorphism. All tumours with PR staining (Allred score ≥2) and marked nuclear pleomorphism were in the high-risk category. No case with PR <2, low survivin (≤15.5%) and nuclear pleomorphism <3 was high-risk. Similarly, 77% of cases were correctly classified into TAILORx categories based on nuclear pleomorphism, survivin, BAG1 and cyclin B1. Ki67 was the only variable that predicted the absolute RS with a cut-off for positivity of 15% (p = 0.003).In conclusion, CART revealed key predictors including proliferation markers, PR and nuclear pleomorphism that correctly classified over two thirds of ER-positive NN cancers into Oncotype DX and TAILORx risk categories. These variables could be used as an alternative to the RT-PCR assay to reduce the number of patients requiring Oncotype DX testing.     

Locoregional recurrence in patients with HER2 positive breast cancer

Literature shows that HER2/neu positive breast cancer cells are more sensitive to radiation-induced apoptosis by targeting the epidermal growth factor receptor family tyrosine kinase. We selected 466 patients with pT1-2 HER2/neu positive tumors who received adjuvant trastuzumab for primary invasive breast cancer. Patients were divided into three groups [Quadrantectomy followed by conventional radiotherapy vs Quadrantectomy followed by Intra-operative radiotherapy with electrons vs Mastectomy without radiotherapy]. After a median follow-up of 52 months, the 5-year cumulative incidence of locoregional recurrence (LRR) was 1.9%, 11.5% and 5.0% respectively (p < 0.01). At the multivariate analysis, extensive perivascular invasion, Luminal B HER2/Progesterone Receptor (PgR) negative status and Quadrantectomy followed by Intra-operative radiotherapy with electrons have significantly increased the risk of LRR. Our results suggest that HER2/neu positive breast cancer might have better outcomes when treated simultaneously with external radiotherapy and trastuzumab. Moreover, we underline the importance of PgR and further new stratification of risk among luminal subtypes.     

The differential effect of BMI on prosthetic versus autogenous breast reconstruction: A multivariate analysis of 12,986 patients

BackgroundThe comparative safety of breast reconstruction in obese patients remains to be clearly defined. This study utilized multi-institutional data to characterize the effect of body mass index (BMI) on breast reconstruction outcomes.MethodsUtilizing Current Procedural Terminology (CPT) codes, patients undergoing tissue expander, pedicled transverse rectus abdominis myocutaneous (TRAM) flap, latissimus dorsi flap, and free flap breast reconstruction were identified in the National Surgical Quality Improvement Program (NSQIP) database. Patients were stratified as obese (BMI ≥ 30) and non-obese (BMI < 30). Overall postoperative morbidity, flap complications, non-flap complications, and reoperation rates were compared among the groups.ResultsOf 12,986 patients who underwent breast reconstruction, 3636 (28.0%) were obese. Overall morbidity was significantly elevated in obese patients across all forms of reconstruction (p < 0.05). BMI was correlated with increased surgical complications for tissue expander, pedicled TRAM, and free flap reconstructions (OR = 1.09, OR = 1.05, OR = 1.10, respectively; p < 0.05). Medical complications were higher in obese patients undergoing tissue expander and pedicled TRAM reconstructions (p = 0.001 and p < 0.001), but no significant difference was observed in latissimus and free flap reconstruction patients. Compared with obese tissue expander recipients, obese patients reconstructed using autologous tissue had higher rates of reoperations (12.8% versus 9.1%), overall morbidity (18.0% versus 9.5%), surgical (12.7% versus 8.3%), and medical complications (9.0% versus 2.2%).ConclusionsThe NSQIP database allows for evaluation and comparison of reconstructive outcomes in the obese population. Increased BMI was associated with higher morbidity in autologous reconstruction than tissue expander reconstruction. Among autologous procedures, latissimus flaps experienced the lowest captured 30 day morbidity.     

Post-mastectomy reconstruction: A risk-stratified comparative analysis of outcomes

IntroductionAlthough breast reconstruction following mastectomy plays a role in the psychological impact of breast cancer, only one in three women undergo reconstruction. Few multi-institutional studies have compared complication profiles of reconstructive patients to non-reconstructive.MethodsUsing the National Surgical Quality Improvement database, all patients undergoing mastectomy from 2006 to 2010, with or without reconstruction, were identified and risk-stratified using propensity scored quintiles. The incidence of complications and comorbidities were compared.ResultsOf 37,723 mastectomies identified, 30% received immediate breast reconstruction. After quintile matching for comorbidities, complications rates between reconstructive and non-reconstructives were similar. This trend was echoed across all quintiles, except in the sub-group with highest comorbidities. Here, the reconstructive patients had significantly more complications than the non-reconstructive (22.8% versus 7.0%, p < 0.001).ConclusionImmediate breast reconstruction is a well-tolerated surgical procedure. However, in patients with high comorbidities, surgeons must carefully counterbalance surgical risks with psychosocial benefits to maximize patient outcomes.Level of evidenceLevel 3     

Intraoperative detection of sentinel lymph nodes in breast cancer patients using ultrasonography-guided direct indocyanine green dye-marking by real-time virtual sonography constructed with three-dimensional computed tomography-lymphography

PurposeThis study aims to determine the utility of ultrasonography (US)-guided direct dye-marking of sentinel lymph nodes (SLNs) by real-time virtual sonography (RVS) constructed with three-dimensional (3D) computed tomography (CT)-lymphography (LG).Patients and methodsWe identified SLNs in 258 clinically node-negative breast cancer patients using an RVS system to display in real time a virtual multiplanar reconstruction CT image obtained from CT volume data corresponding to the same cross-sectional image from US. CT volume data were obtained using our original 3D CT-LG, which accurately detects SLNs in breast cancer. We then perform US-guided dye-marking close to SLNs using indocyanine green (ICG). Subsequently, indigo carmine blue dye was injected into the subareolar and peritumoral areas around each primary tumor. All patients underwent SLN biopsy and SLN metastases were examined pathologically.ResultsIn all 258 patients, we were able to detect the same SLNs visualized on 3D CT-LG, using the RVS system. We detected ICG close to SLNs in 257 of 258 patients (99.6%) during SLN biopsy. In 25 patients (9%), we failed to follow the blue lymphatic route stained by indigo carmine and SLNs were not stained by indigo carmine, but easily detected SLNs by ICG marking.ConclusionUS-guided direct ICG dye-marking of SLNs using this RVS system seems useful for the detection of SLNs, allowing easy detection of SLNs even when the stained lymphatic route is not followed.     

Phase II study of liposome-encapsulated doxorubicin plus cyclophosphamide,followed by sequential trastuzumab plus docetaxel as primary systemic therapy for breast cancer patients with HER2 overexpression or amplification

Purpose of the studyTrastuzumab combined with sequential chemotherapy with taxanes and anthracyclines as primary systemic therapy achieved high rates of pathologic complete response (pCR). Non-pegylated liposome-encapsulated doxorubicin (NPLD) has shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab with sequential chemotherapy for early or locally advanced HER2 positive BC.MethodsPreoperative treatment included NPLD (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Primary endpoint was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Clinical staging was exploratory evaluated by CT-PET.Results43 pts were treated from december 2005 to September 2011, 39 of them were evaluable for the purpose of study. Median age was 53 years (range: 31–78), the majority of pts had tumour stage cT2 (63%), tumour grade 3 (86%), clinical nodes involvement N+ (77%), ER positive (56%) and Ki-67 ≥20% (77%). pCR was reported in 19 (49%) of 39 pts. There was an association between Ki-67 ≥20% at baseline and pCR (p = 0.018). No cardiac toxicity or discontinuation of trastuzumab was reported. CT-PET modified the clinical stage for 10 patients showing new loco-regional lymph nodes.ConclusionsThis study confirms that integrating anti-HER2 therapy in primary treatment for HER2 positive breast cancer is active. NPLD is a safe option to minimize cardiotoxicity.     

Randomized phase II study of sunitinib versus standard of care for patients with previously treated advanced triple-negative breast cancer

PurposeThis randomized, open-label phase II study compared the efficacy of sunitinib monotherapy with that of single-agent standard-of-care (SOC) chemotherapy in patients with previously treated advanced triple-negative breast cancer (TNBC).MethodsPatients with advanced TNBC, relapsed after anthracycline- and taxane-based chemotherapy, were randomized to receive either sunitinib (37.5 mg/day) or the investigator's choice of SOC therapy. Progression-free survival was the primary endpoint.ResultsMedian progression-free survival was 2.0 months with sunitinib and 2.7 months with SOC chemotherapy (one-sided P = 0.888). Median overall survival was not prolonged with sunitinib (9.4 months) compared with SOC chemotherapy (10.5 months; one-sided P = 0.839). The objective response rate was 3% with sunitinib and 7% with SOC chemotherapy (one-sided P = 0.962).ConclusionsSunitinib monotherapy did not improve efficacy compared with SOC chemotherapy in patients with previously treated advanced TNBC, for which identification of effective treatments and therapeutic targets remains an urgent need.Trial registrationNCT00246571.     

Morphometric and Histological Study of Breast Lesions with Special Reference to Proliferative Activity and Invasiveness

Breast carcinoma is the most common cause of carcinoma death in women. Sometimes, difficulty arises to differentiate between premalignant lesions and carcinoma by routine histopathology. Our study was done to establish the role of morphometry and immunohistochemistry to solve this problem. In this study, total 60 cases of different breast lesions were included and 10 controls were also included to compare the results with the normal findings. They were studied by hematoxylin and eosin-stained sections for morphometry and routine histological study; as well as by proliferative markers such as proliferating cell nuclear antigen and p53. Invasiveness was studied using immunohistochemical staining with 34 βE12 monoclonal antibody. Statistically significant differences were found in morphometric parameters and in expression of proliferative markers between most of them. Morphometry and immunohistochemistry help in the proper diagnosis of different breast lesions that lie in the gray zone on routine histopathology.     

The impact of lobular and ductal breast cancer histology on the metastatic behavior and long term survival of breast cancer patients

The aim of the study was to evaluate the long-term survival of patients with invasive lobular carcinomas (ILC) and invasive ductal carcinomas (IDC) and the metastatic behavior of these two disease entities. Originally, all consecutive patients with pure lobular invasive breast cancers diagnosed between 1990 and 1999 in the area served by the Tampere University Hospital and their matched IDC controls were identified and re-evaluated histopathologically in this follow-up study, resulting in a total of 243 ILCs and 243 IDCs. Data on recurrences and survival were collected until the end of year 2009. Statistical analyses including Kaplan–Meier method, log-rank test, Fisher's exact test and Cox regression analysis were performed with the PASW Statistics 18.0 computer program. P-values of <0.05 were considered statistically significant.Within the mean follow-up time of 10.04 years, locoregional recurrences were significantly more common among the ILCs than IDCs (35 vs. 20, p = 0.04), but no differences in the total number of distant recurrences or bilaterality were observed. However, when the first distant recurrence sites were studied, ILC patients had significantly less lung metastases (p = 0.04), but more skin metastases (p = 0.04). During the whole follow-up period IDCs metastasized significantly more frequently to the lungs (p = 0.002), whereas gastrointestinal metastases were more common among ILCs (p = 0.02). Although the known favorable prognostic factors (hormone receptor positivity, low grade, low s-phase) were more common for the ILCs, the disease-free survival, the overall survival and the survival after recurrence did not differ between the groups. However, the Cox-regression model showed significantly worse survival for ILCs after adjusting for age, TNM-status, grade and ER-positivity (p = 0.004).In conclusion, ILC and IDC differ in respect for visceral metastases. Despite the known favorable prognostic factors and originally favorable survival, patients with lobular histology appear to have a worse survival in the multivariate analysis after a prolonged follow-up.     

Disentangling breast cancer patients' perceptions and experiences with regard to endocrine therapy: Nature and relevance for non-adherence

Background & study aimsAdjuvant endocrine therapy effectively prevents recurrence and progression of estrogen-receptor positive breast cancer. However, studies reveal substantial non-adherence. The objective was therefore to identify the nature of the experiences and beliefs of women treated with endocrine therapy in an attempt to find potential determinants of non-adherence.MethodOnline Focus Groups (OFGs) and individual interviews were conducted with 37 women who were treated with endocrine therapy. Sixty-three statements derived from the OFGs and 11 belief items from the Beliefs about Medicines Questionnaire (BMQ) were used in a Q-sorting task conducted with 14 of the women. The quantitative Q-sorting data were statistically analyzed with Hierarchical Cluster Analysis.ResultsA six cluster solution was revealed that included the clusters ‘information’, ‘efficacy’, ‘tenacity’, ‘coping’, ‘side effects’ and ‘usage’. Women's own experiences and perceptions were not clearly delineated from the beliefs measured with the BMQ. However, women judged their own experiences and perceptions with regard to endocrine therapy as more relevant for adherence than the BMQ beliefs.ConclusionIn order to understand and to improve women's adherence to endocrine therapy, women's own perceptions and experiences about endocrine therapy should be targeted in addition to common beliefs that apply to a wide range of medicines.