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.

Surgical Tumor Resection Deregulates Hallmarks of Cancer in Resected Tissue and the Surrounding Microenvironment.

Surgery exposes tumor tissue to severe hypoxia and mechanical stress leading to rapid gene expression changes in the tumor and its microenvironment, which remain poorly characterized. We biopsied tumor and adjacent normal tissues from patients with breast (n = 81) and head/neck squamous cancers (HNSC; n = 10) at the beginning (A), during (B), and end of surgery (C). Tumor/normal RNA from 46/81 patients with breast cancer was subjected to mRNA-Seq using Illumina short-read technology, and from nine patients with HNSC to whole-transcriptome microarray with Illumina BeadArray. Pathways and genes involved in 7 of 10 known cancer hallmarks, namely, tumor-promoting inflammation (TNF-A, NFK-B, IL18 pathways), activation of invasion and migration (various extracellular matrix-related pathways, cell migration), sustained proliferative signaling (K-Ras Signaling), evasion of growth suppressors (P53 signaling, regulation of cell death), deregulating cellular energetics (response to lipid, secreted factors, and adipogenesis), inducing angiogenesis (hypoxia signaling, myogenesis), and avoiding immune destruction (CTLA4 and PDL1) were significantly deregulated during surgical resection (time points A vs. B vs. C). These findings were validated using NanoString assays in independent pre/intra/post-operative breast cancer samples from 48 patients. In a comparison of gene expression data from biopsy (analogous to time point A) with surgical resection samples (analogous to time point C) from The Cancer Genome Atlas study, the top deregulated genes were the same as identified in our analysis, in five of the seven studied cancer types. This study suggests that surgical extirpation deregulates the hallmarks of cancer in primary tumors and adjacent normal tissue across different cancers. IMPLICATIONS: Surgery deregulates hallmarks of cancer in human tissue.

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.

Effectiveness of a Decision Aid Plus Standard Care in Surgical Management Among Patients With Early Breast Cancer: A Randomized Clinical Trial.

Importance: Patients with early breast cancer must choose between undergoing breast conservation surgery or mastectomy. This decision is often difficult as there are trade-offs between breast conservation and adverse effects, and women with higher decisional conflict have a harder time choosing the therapy that suits their preferences. Objective: To study the impact of a decision aid with a patient preference assessment tool for surgical decision-making on patients' decisional conflict scale (DCS) score. Design, Setting, and Participants: This 3-group randomized clinical trial was conducted between June 2017 and December 2019 at a single high-volume tertiary care cancer center in Mumbai, India. A research questionnaire comprising 16 questions answered on a Likert scale (from 1, strongly agree, to 5, strongly disagree) was used to measure DCS scores and other secondary psychological variables, with higher scores indicating more decisional conflict. The Navya Patient Preference Tool (Navya-PPT) was developed as a survey-based presentation of evidence in an adaptive, conjoint analysis-based module for and trade-offs between cosmesis, adverse effects of radiotherapy, and cost of mandatory radiation following breast-conserving surgery. Adult patients with histologically proven early breast cancer (cT1-2, N0-1) who were eligible for breast-conserving surgery as per clinicoradiological assessment were included. Those who were pregnant or unable to read the research questionnaire or who had bilateral breast cancer were excluded. Data were analyzed from January to June 2020. Interventions: Patients were randomized 1:1:1 to study groups: standard care including clinical explanation about surgery (control), standard care plus the Navya-PPT provided to the patient alone (solo group), and standard care plus the Navya-PPT provided to the patient and a caregiver (joint group). Main Outcomes and Measures: The primary end point of the study was DCS score. The study was 80% powered with 2-sided α = .01 to detect an effect size of 0.25 measured by Cohen d, F test analysis of variance, and fixed effects. Results: A total of 245 female patients (median [range] age, 48 [23-76] years) were randomized (82 to control, 83 to the solo group, and 80 to the joint group). The median (range) pathological tumor size was 2.5 (0-6) cm. A total of 153 participants (62.4%) had pN0 disease, 185 (75.5%) were hormone receptor positive, 197 (80.4%) were human epidermal growth factor receptor 2 negative, 144 (58.6%) were of middle or lower socioeconomic status, and 114 (46.5%) had an education level lower than a college degree. DCS score was significantly reduced in the solo group compared with control (1.34 vs 1.66, respectively; Cohen d, 0.50; SD, 0.31; P < .001) and the joint group compared with control (1.31 vs 1.66, respectively; Cohen d, 0.54; SD, 0.31; P < .001). Conclusions and Relevance: The results of this study demonstrated lower decisional conflict as measured by DCS score following use of the online, self-administered Navya-PPT among patients with early breast cancer choosing between breast-conserving surgery vs mastectomy. Trial Registration: Clinical Trials Registry of India Identifier: CTRI/2017/11/010480.

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].

Determinants of pathological complete response to neoadjuvant chemotherapy in breast cancer: A single-institution experience.

Background: Neoadjuvant chemotherapy (NACT) is routinely used in all cases of locally advanced breast cancer and some cases of early breast cancer. We previously reported a pathological complete response (pCR) rate of 8.3%. With the increasing use of taxanes and human epidermal growth factor receptor 2 (HER2)-directed NACT, we conducted this study to understand the current pCR rate and its determinants. Methods: A prospective database of breast cancer patients who underwent NACT followed by surgery between January and December 2017 was evaluated. Results: Of the 664 patients, 87.7% were cT3/T4, 91.6% were grade III, and 89.8% were node-positive at presentation (54.4% cN1, 35.4% cN2). The median age was 47 years; median pre-NACT clinical tumor size was 5.5 cm. Molecular subclassification was 30.3% hormone receptor positive (HR+) HER2-, 18.4% HR+HER2+, 14.9% HR-HER2+, and 31.6% triple negative (TN). Both anthracyclines and taxanes were given preoperatively in 31.2% patients whereas 58.5% of HER2 positive patients received HER2-targeted NACT. The overall pCR rate was 22.4% (149/664), 9.3% in HR+HER2-, 15.6% in HR+HER2+, 35.4% in HR-HER2+, and 33.4% in TN. On univariate analysis, duration of NACT (P < 0.001), cN stage at presentation (P = 0.022), HR status (P < 0.001), and lymphovascular invasion (P < 0.001) were associated with pCR. On logistic regression, HR negative status (Odds ratio [OR] 3.314, P < 0.001), longer duration of NACT (OR 2.332, P < 0.001), cN2 stage (OR 0.57, P = 0.012), and HER2 negativity (OR 1.583, P = 0.034) were significantly associated with pCR. Conclusion: Response to chemotherapy depends on molecular subtype and duration of NACT. A low rate of pCR in the HR+ subgroup of patients warrants reconsideration of neoadjuvant strategies.

Synchronous and Metachronous Breast and Ovarian Cancers: Experience from a Single Tertiary Care Cancer Centre in India.

Women with either breast cancer (BC) or ovarian cancer (OC) have a 1.5-2 times higher risk of developing the other. Discerning discrete primaries versus metastases from either can be challenging. Clinico-pathological and outcome details of patients diagnosed with both BC and OC from December 1994 to August 2018 were retrospectively evaluated at a single tertiary cancer centre. We report the pattern of presentation and recurrences with case-based illustrations. Out of 139 patients, presentation was BC-first in 66.2%, OC-first in 24.5% and synchronous cancers (SC) in 9.3% of women. The median age at diagnosis in BC-first, OC-first and SC was 42 years, 48 years and 49 years, respectively. The most common histological subtype was invasive breast carcinoma-no special type (74.8%) in BC and serous cystadenocarcinoma (81.3%) in OC. BC presented at an early stage in 67.6% while OC presented at an advanced stage in 48.2% of patients. Germline mutation results were available in 82% with 61.4% of the cohort exhibiting a mutation- BRCA1 mutation being the most common. The median time to development of second cancer was 77.4 months and 39.4 months in BC-first and OC-first, respectively. At a median follow-up of 9.47 years, disease-free survival was 32.6%, 32.4% and 30.8% in BC-first, OC-first and SC, respectively (p < 0.001). In hereditary breast and ovarian cancer, BC-first patients have a better prognosis while synchronous malignancies have worse oncological outcomes. Deaths are mainly due to OC progression. Appropriate surveillance and prophylactic intervention in young patients with breast cancer may improve overall outcomes.

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.

Sterilization Rate of the Axilla After Neoadjuvant Chemotherapy: The Scope for Conservative Surgery.

PURPOSE: The role of axillary conservation after neoadjuvant chemotherapy (NACT) is debatable. We routinely carry out complete axillary lymph node dissection (ALND). This study was conducted to understand the pathologic axillary complete response (pAxCR) after NACT. MATERIALS AND METHODS: We evaluated a prospective database of patients with breast cancer who underwent surgery after NACT in the year 2017 at our institution. NACT was administered to downstage locally advanced breast cancer or facilitate breast-conservation surgery. RESULTS: Of 793 patients who underwent surgery after NACT, 97(12.2%) had cN0 disease, 407 (51.3%) had cN1, 262 (32%) had cN2, and 27 (3.4%) had cN3 at presentation. Eighty-eight patients (11.1%) had cT1-2 primary tumor stage, and 623 patients (78.6%) had cT3-4 primary tumor stage; primary tumor stage details were unavailable for 82 patients (10.3%). The median age was 46 years (range, 21-74 years). On histopathology, the overall pAxCR rate was 52.8%. In the cN1 and cN2 settings, 58.7% and 36.6% of patients achieved ypN0 status, respectively. The overall pathologic complete response rate was 22.64% (161 of 711 patients). On univariable analysis, cN stage, histologic grade, hormone receptor status, NACT duration, and lymphovascular invasion were significantly associated with pAxCR (P <.001). On logistic regression, prechemotherapy cN status (odds ratio [OR], 3.08; 95% CI, 2.18 to 4.37; P <.001), estrogen and progesterone receptor status (OR, 0.34; 95% CI, 0.3 to 0.4; P <.001), and administration of both chemotherapy regimens preoperatively (OR, 0.66; 95% CI, 0.45 to 0.97; P <.05) predicted pAxCR. CONCLUSION: At least half of patients with cN1 and a third of patients with cN2 breast cancer who develop pAxCR may be suitable candidates for axillary conservation. A careful postchemotherapy assessment followed by a conservative axillary procedure may be an alternative to ALND, but this needs to be studied prospectively.

Merits of Level III Axillary Dissection in Node-Positive Breast Cancer: A Prospective, Single-Institution Study From India.

PURPOSE: A complete axillary lymph node (ALN) dissection is therapeutic in node-positive breast cancer. Presently, there is no international consensus regarding anatomic levels to be addressed in complete axillary dissection. We assessed the burden of disease in level III axilla. MATERIALS AND METHODS: A prospectively maintained database was assessed for 1,591 consecutive patients with nonmetastatic breast cancer registered at Tata Memorial Center, Mumbai, between January 2009 and December 2014. RESULTS: A median of four (zero to 20) level III ALNs were dissected and a median of two (one to 17) nodes were positive. A total of 27.3% (434 of 1,591) patients had level III ALN metastasis, and 4.7% of patients had positive interpectoral nodes. Some 53.2% of patients had level III metastases in the presence of four or more positive level I and II ALNs. A total of 9.4% of patients had level III involvement when one to three ALNs were positive in level I and II ( P < .001). Some 53.2% of patients had level III metastases in the presence of four or more positive level I and II ALNs. On logistic regression analysis, four or more positive ALNs in level I or II ( P < .001), inner/central quadrant tumor location ( P = .013), and perinodal extension ( P < .001) were associated with level III ALN involvement. At a median follow-up of 36 months, the disease-free survival was significantly worse for level III ALN metastases on univariate analysis ( P < .001). On multivariate Cox regression analysis, histologic grade ( P = .006), four or more positive ALNs ( P < .001), hormone receptor status ( P < .001), and tumor size ( P = .037) were independent prognostic factors for disease-free survival. CONCLUSION: The axillary nodal burden is high in patients with breast cancer in developing countries like India. One of two women with four or more positive level I and II ALNs may have residual disease in level III if it is not cleared during surgery. Intraoperative interpectoral space clearance should be considered in the presence of either palpable interpectoral lymph nodes or multiple positive ALNs.

Breast cancer in a tertiary cancer center in India - An audit, with outcome analysis.

BACKGROUND: Survival studies may serve as benchmarks to develop cancer-related policies and estimate baseline survival rates in a given patient population. MATERIALS AND METHODS: We carried out a retrospective audit of cases managed in 2009 and now report the disease-free survival (DFS) in early breast cancer (EBC) and locally advanced breast cancer (LABC) in patients registered at a tertiary cancer center in India. RESULTS: The study included 2192 patients with breast cancer with ages ranging from 18 years to 94 years with a median of 50 years. Of these, 888 (40.5%) were EBCs Stage I and II, 833 (38%) were LABCs (Stage III), and 471 (21.5%) were de novo metastatic or relapsed cancers at presentation. The 5-year DFS in the women with EBC was 85.5% and in LABC, it was 67.7%, P < 0.001. The factors adversely affecting DFS in EBC were node metastasis (P < 0.001), higher metastatic nodes (P < 0.001), hormone receptor negativity (P = 0.001), and human epidermal growth factor receptor 2 (Her2neu) positivity (P = 0.033). In the multivariate Cox regression analysis in EBC, node-positive status (hazard ratio [HR] 2.28, 95% confidence interval [CI] 1.51-3.45, P < 0.001) and hormone receptor negative tumors (HR 1.96, 95% CI 1.30-2.94, P = 0.001) significantly affected DFS in EBC. The factors adversely affecting DFS in LABC in the univariate analysis were node metastasis (P < 0.001), increasing numbers of nodes (P < 0.001), presence of lymphovascular emboli (LVE) (P < 0.01), mastectomy (P < 0.001), and Her2neu positivity (P = 0.03). In the multivariate Cox regression analysis, node positivity (HR 2.96, 95% CI 2.04-4.29, P < 0.0001), presence of LVE (HR 1.47, 95% CI 1.06-2.04, P = 0.023), and mastectomy (HR 1.49, 95% CI 1.06-2.10, P = 0.023) adversely impacted DFS in LABC. CONCLUSIONS: The survival rates in this study are equal to the documented global rates; nodal disease burden emerged as the most important prognostic factor. In addition, in EBCs, a lack of hormone receptor expression and in LABC, Her2neu overexpression appear to worsen the outcome.

Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial.

PURPOSE: Many nonrandomized studies have suggested better outcome for patients with breast cancer who undergo surgery during the luteal (progestogenic) phase of their menstrual cycle, but this is controversial. We investigated the effect of a single preoperative injection of hydroxyprogesterone in women with operable breast cancer (OBC) in a randomized controlled trial (ClinicalTrials.gov identifier, NCT00123669). PATIENTS AND METHODS: One thousand patients with OBC were randomly assigned to receive surgery or an intramuscular injection of depot hydroxyprogesterone 500 mg 5 to 14 days before surgery. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), respectively. An analysis by axillary lymph node status was preplanned. RESULTS: At a median follow-up of 65 months among 976 eligible patients, 273 recurrences and 202 deaths were recorded. In the progesterone group versus control group, 5-year DFS and OS rates were 73.9% v 70.2% (hazard ratio [HR], 0.87; 95% CI, 0.68 to 1.09; P = .23) and 80.2% v 78.4% (HR, 0.92; 95% CI, 0.69 to 1.21; P = .53), respectively. In 471 node-positive patients, the 5-year DFS and OS rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P = .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P = .04), respectively. In multivariate analysis, DFS was significantly improved with progesterone in node-positive patients (adjusted HR, 0.71; 95% CI, 0.53 to 0.95; P = .02), whereas there was no significant effect in node-negative patients (P for interaction = .04). CONCLUSION: A single injection of hydroxyprogesterone before surgery did not improve outcomes in all women with OBC. This intervention showed significant improvement in node-positive women that may be considered hypothesis generating. If replicated in other studies, this could be a simple and inexpensive intervention, especially in developing countries where the incidence of lymph node metastasis is high.