Tata Memorial Centre Evidence Based Management of Breast cancer.

ABSTRACT: The incidence of breast cancer is increasing rapidly in urban India due to the changing lifestyle and exposure to risk factors. Diagnosis at an advanced stage and in younger women are the most concerning issues of breast cancer in India. Lack of awareness and social taboos related to cancer diagnosis make women feel hesitant to seek timely medical advice. As almost half of women develop breast cancer at an age younger than 50 years, breast cancer diagnosis poses a huge financial burden on the household and impacts the entire family. Moreover, inaccessibility, unaffordability, and high out-of-pocket expenditure make this situation grimmer. Women find it difficult to get quality cancer care closer to their homes and end up traveling long distances for seeking treatment. Significant differences in the cancer epidemiology compared to the west make the adoption of western breast cancer management guidelines challenging for Indian women. In this article, we intend to provide a comprehensive review of the management of breast cancer from diagnosis to treatment for both early and advanced stages from the perspective of low-middle-income countries. Starting with a brief introduction to epidemiology and guidelines for diagnostic modalities (imaging and pathology), treatment has been discussed for early breast cancer (EBC), locally advanced, and MBC. In-depth information on loco-regional and systemic therapy has been provided focusing on standard treatment protocols as well as scenarios where treatment can be de-escalated or escalated.

Validation of PREDICT Version 2.2 in a Retrospective Cohort of Indian Women With Operable Breast Cancer.

PURPOSE: Online prediction models that use known prognostic factors in breast cancer (BC) are routinely used to assist in decisions for adjuvant therapy. PREDICT Version 2.2 (P2.2) is one such online tool, which uses tumor size, lymph node involvement, grade, age, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, and Ki67. We performed an external validation in a retrospective cohort of patients treated at a tertiary center in India. METHODS: Women with operable BC between 2008 and 2016 with nonmetastatic, T1-T2 invasive, and HER2 receptor-negative BC and with available 5-year overall survival (OS) data were selected. Median predicted 5-year OS rates were used to calculate predicted events for the whole cohort and subgroups. The chi-square test was used to evaluate the goodness of fit of the tool. RESULTS: Of 11,760 cases registered between 2008 and 2016, 2,783 (23.66%) eligible patients with a median age of 50 (26-70) years and a median pT size of 2.5 (0.1-5) cm, 2,037 (73.19%) with grade 3 tumors, 1,172 (42.11%) with node-positive disease, 817 (29.35%) with triple-negative breast cancer, and 1,966 (70.64%) with HR-positive BC were included in the analysis. The observed 5-year OS and predicted 5-year OS in the whole cohort were 94.8% and 90.00%, respectively, with an absolute difference of 4.8% (95% CI, 3.417 to 6.198, P < .001). The observed 5-year OS and predicted 5-year OS were also different in various subgroups. CONCLUSION: PREDICT version 2.2 overestimated the number of deaths, with lower predicted 5-year OS compared with the observed value, in this retrospective Indian cohort. The reasons for this discrepancy could be differing biologic characteristics and possible selection bias in our cohort. We recommend a prospective validation of PREDICT in Indian patients and advocate caution in its use until such validation is achieved.

Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer.

PURPOSE: Preventing metastases by using perioperative interventions has not been adequately explored. Local anesthesia blocks voltage-gated sodium channels and thereby prevents activation of prometastatic pathways. We conducted an open-label, multicenter randomized trial to test the impact of presurgical, peritumoral infiltration of local anesthesia on disease-free survival (DFS). METHODS: Women with early breast cancer planned for upfront surgery without prior neoadjuvant treatment were randomly assigned to receive peritumoral injection of 0.5% lidocaine, 7-10 minutes before surgery (local anesthetics [LA] arm) or surgery without lidocaine (no LA arm). Random assignment was stratified by menopausal status, tumor size, and center. Participants received standard postoperative adjuvant treatment. Primary and secondary end points were DFS and overall survival (OS), respectively. RESULTS: Excluding eligibility violations, 1,583 of 1,600 randomly assigned patients were included in this analysis (LA, 796; no LA, 804). At a median follow-up of 68 months, there were 255 DFS events (LA, 109; no LA, 146) and 189 deaths (LA, 79; no LA, 110). In LA and no LA arms, 5-year DFS rates were 86.6% and 82.6% (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95; P = .017) and 5-year OS rates were 90.1% and 86.4%, respectively (HR, 0.71; 95% CI, 0.53 to 0.94; P = .019). The impact of LA was similar in subgroups defined by menopausal status, tumor size, nodal metastases, and hormone receptor and human epidermal growth factor receptor 2 status. Using competing risk analyses, in LA and no LA arms, 5-year cumulative incidence rates of locoregional recurrence were 3.4% and 4.5% (HR, 0.68; 95% CI, 0.41 to 1.11), and distant recurrence rates were 8.5% and 11.6%, respectively (HR, 0.73; 95% CI, 0.53 to 0.99). There were no adverse events because of lidocaine injection. CONCLUSION: Peritumoral injection of lidocaine before breast cancer surgery significantly increases DFS and OS. Altering events at the time of surgery can prevent metastases in early breast cancer (CTRI/2014/11/005228).[Media: see text].

Access to HER2-targeted therapy at a tertiary care center in India: An evolution.

Background: In a previous retrospective audit from our institution we reported that patients had limited access to HER2-targeted therapy due to financial constraints. Subsequently, the advent of biosimilar versions of trastuzumab and philanthropic support has potentially changed this situation. Herein, we reanalyzed and reported access to HER2-targeted therapy in a more recent cohort of patients. Methods: Medical records of new breast cancer patients registered in one calendar year were retrospectively reviewed, supplemented by online pharmacy data to extract information on receptor status, use of HER2-targeted therapy, and other relevant variables. Since not all HER2 immunohistochemistry (IHC) 2+ tumors underwent fluorescent in-situ hybridization (FISH) testing, we estimated the probable HER2 amplified from this group based on a FISH amplified fraction in those HER2 2+ tumors who did undergo FISH. Results: Between January 2016 and December 2016, 4717 new BC patients were registered at our institution, of whom 729 (20.04%) had HER2 IHC 3+ tumors while 641 (17.62%) had HER2 IHC 2+ tumors. The final number of HER2 overexpressing/amplified tumors was estimated to be 928 (729 HER2 IHC 3+, 105 known FISH amplified, and 94 estimated FISH amplified), of whom 831 received treatment at our institution. Overall 474 (57.03%, 95% confidence interval [CI] 53.6-60.4) of these 831 patients received trastuzumab for durations ranging from 12 weeks to 12 months in the (neo)adjuvant setting or other durations in metastatic setting compared to 8.61% (95% CI 6.2-11.6) usage of HER2-targeted therapy in the 2008 cohort. Conclusion: Access to HER2-targeted therapy has substantially increased among patients treated at a public hospital in the past decade, likely due to the advent of biosimilars, the use of shorter duration adjuvant regimens, and philanthropic support. However, further efforts are required to achieve universal access to this potentially life-saving treatment.

Sentinel Node Biopsy Versus Low Axillary Sampling in Predicting Nodal Status of Postchemotherapy Axilla in Women With Breast Cancer.

PURPOSE: We tested low axillary sampling (LAS) and sentinel node biopsy (SNB) performed in the same patient to predict axillary nodal status post-neoadjuvant chemotherapy (NACT) in women undergoing elective breast surgery, clinically N0 after NACT. PATIENTS AND METHODS: A total of 751 women clinically node negative post-NACT underwent LAS (excision of lymph node [LN] and fat below first intercostobrachial nerve). Of these women, 730 also underwent SNB by dual technique (methylene blue plus radioisotope). SNB (defined as targeted plus palpable LNs) and LAS specimens were distinctly examined for metastasis. All patients underwent completion axillary lymph node dissection. Post-NACT, 290 (38.6%) of 751 women had residual positive lymph nodes on pathology. RESULTS: The median clinical tumor size was 5 cm (range, 1-15 cm), and 533 (71%) of patients were N1 or N2 at presentation. Targeted sentinel node (SN) identification was 85.7% (626 of 730; median, two LNs); SN with palpable nodes was found in 95.2% (695 of 730; median, five LNs); LAS node was identified in 98.5% (740 of 751; median, seven LNs). In all but one case, the SN was found within the LAS specimen. The false negative rate (FNR) of SNB (blue, hot, and adjacent palpable nodes) was 19.7% (47 of 238; one-sided 95% CI upper limit, 24.0), compared with an FNR of 9.9% for LAS (29 of 292; one-sided 95% CI upper limit, 12.8; P < .001). If SNB was confined to blue/hot node, excluding adjacent palpable nodes, the FNR was 31.6% (74 of 234; one-sided 95% CI upper limit, 36.6). The FNR could be brought down to < 8.8% if three or more LNs were identified by LAS. CONCLUSION: LAS is superior to SNB in identification rate, FNR, and negative predictive value in predicting node-negative axilla post-NACT. LAS can be safely used to predict negative axilla with < 10% chance of leaving residual disease.

Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomised controlled trial.

BACKGROUND: The role of locoregional treatment in women with metastatic breast cancer at first presentation is unclear. Preclinical evidence suggests that such treatment might help the growth of metastatic disease, whereas many retrospective analyses in clinical cohorts have suggested a favourable effect of locoregional treatment in these patients. We aimed to compare the effect of locoregional treatment with no treatment on outcome in women with metastatic breast cancer at initial presentation. METHODS: In this open-label, randomised controlled trial, we recruited previously untreated patients (≤65 years of age with an estimated remaining life expectancy of at least 1 year) presenting with de-novo metastatic breast cancer from Tata Memorial Centre, Mumbai, India. Patients were randomly assigned (1:1) to receive locoregional treatment directed at their primary breast tumour and axillary lymph nodes, or no locoregional treatment, by a computer-generated block randomisation sequence (block size of four). Randomisation was stratified by site of distant metastases, number of metastatic lesions, and hormone receptor status. Patients with resectable primary tumour in the breast that could be treated with endocrine therapy were randomly assigned upfront, whereas those with an unresectable primary tumour were planned for chemotherapy before randomisation. Of the patients who had chemotherapy before randomisation, we randomly assigned patients who had an objective tumour response after six to eight cycles of chemotherapy. The primary endpoint was overall survival analysed by intention to treat. This study is registered with ClinicalTrials.gov, NCT00193778. FINDINGS: Between Feb 7, 2005, and Jan 18, 2013, of the 716 women presenting with de-novo metastatic breast cancer, we randomly assigned 350 patients: 173 to locoregional treatment and 177 to no locoregional treatment. At data cut-off of Nov 1, 2013, median follow-up was 23 months (IQR 12·2-38·7) with 235 deaths (locoregional treatment n=118, no locoregional treatment n=117). Median overall survival was 19·2 months (95% CI 15·98-22·46) in the locoregional treatment group and 20·5 months (16·96-23·98) in the no-locoregional treatment group (HR 1·04, 95% CI 0·81-1·34; p=0·79), and the corresponding 2-year overall survival was 41·9% (95% CI 33·9-49·7) in the locoregional treatment group and 43·0% (35·2-50·8) in the no locoregional treatment group. The only adverse event noted was wound infection related to surgery in one patient in the locoregional treatment group. INTERPRETATION: There is no evidence to suggest that locoregional treatment of the primary tumour affects overall survival in patients with metastatic breast cancer at initial presentation who have responded to front-line chemotherapy, and this procedure should not be part of routine practice.

High prevalence and correlates of low bone mineral density in young adults with sickle cell disease.

Sickle cell disease (SCD) is a prevalent genetic disorder in which sickle hemoglobin leads to tissue hypoxia and adverse effects on bone. Published studies suggest that children with SCD often have undiagnosed osteopenia or osteoporosis. Minimal data exist on the prevalence of low bone mineral density (BMD) in adults. Our objective was to describe the prevalence of osteopenia and osteoporosis in adults with SCD and to identify patient or disease characteristics associated with low BMD. We conducted a cross-sectional study of adults with SCD. Through questionnaires, we collected data about disease course and osteoporosis risk factors. Patients underwent dual X-ray absorptiometry (DXA) measurement of BMD at the hip, spine, and forearm and sampling of blood and urine for markers of bone turnover, sickle cell disease severity, and secondary causes of osteoporosis. Our main outcome measure was prevalence of osteopenia and osteoporosis as defined by WHO criteria. Of 32 adults with SCD (14 men and 18 women) with a mean age of 34 years, 72% (95% confidence interval 53-86%) had low BMD at one or more anatomic sites. Thirteen patients were classified as osteoporotic and 10 as osteopenic. The prevalence of low BMD was greatest in the lumbar spine (66% of patients). Significant correlates of decreased BMD included low BMI (P < 0.01), male sex (P = 0.02), and low serum zinc concentrations (P < 0.01). The prevalence of osteopenia and osteoporosis in young adults with SCD is extremely high. Further research is needed to address fracture risk and therapeutic interventions.

SAGE transcript profiles of normal primary human hepatocytes expressing oncogenic hepatitis B virus X protein.

Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). HBV encodes an oncogenic HBx gene that functions as a transcriptional coactivator of multiple cellular genes. To understand the role(s) of HBx in the early genesis of HCC, we systematically analyzed gene expression profiles by serial analysis of gene expression (SAGE) in freshly isolated human primary hepatocytes infected with a replication-defective adenovirus containing HBx. A total of 19,501 sequence tags (representing 1443 unique transcripts) were analyzed, which provide a distribution of a transcriptome characteristic of normal hepatocytes and a profile associated with HBx expression. Examples of the targeted genes were confirmed by the Megarray analysis with a significant correlation between quantitative SAGE and Megarray (r = 0.8, P < 0.005). In HBx-expressing hepatocytes, a total of 57 transcripts (3.9%) were induced, and 46 transcripts (3.3%) were repressed by more than fivefold. Interestingly, most of the HBx-up-regulated transcripts can be clustered into three major classes, including genes that encode ribosomal proteins, transcription factors with zinc-finger motifs, and proteins associated with protein degradation pathways. These results suggest that HBx may function as a major regulator in common cellular pathways that, in turn, regulate protein synthesis, gene transcription, and protein degradation.