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Background- Dissemination of cancer cells and their colonization at distant sites (metastases) is the primary cause of death in patients with solid tumors. Despite of popular theories of cancer metastases, there are several lacunae in our understanding of extent of Metastatic Disease at Presentation (MDP). The aim of this study was to evaluate if organ sites could be grouped together based on the available knowledge extent of lympho-vascular communication (LVC) and probable respiratory pressure changes they undergo and whether this correlated with incidence of MDP. Methods- We analyzed a prospectively maintained database of patients with solid tumors presenting between January and December 2017 at our tertiary care cancer center. The tumors were hypothetically divided into four regions (R) depending on extent of LVC and respiratory pressure changes. All patients had clinico-radiological staging after pathological confirmation of cancer. The hypothetical region grouping R1-R4 was independently evaluated by unsupervised k-means clustering. The incidence of MDP was compared in subgroups defined by primary tumor stage, anatomical region, histology, gender, and age using logistic regression. Results- Of 17,467 patients included with median age 54 years, 6714 (38.4%) had MDP. The incidence of M1 disease in R1 vs R2 vs R3 vs R4 regions, older (>50 years) vs younger Conclusion- Primary anatomical regions defined by LVC and respiratory pressure changes; primary tumor histology (type and grade) and male gender are significant determinants of MDP in solid tumors. Region grouping of solid organs based on extent of lymphaticovenous communications and rhythmic respiratory pressure changes and % MDP Citation Format: Rajendra Badwe, Shalaka Joshi, Rohini Hawaldar, Rohan Chaubal, Atanu Bhattacharjee, Vaibhav Vanmali, Nita S. Nair, Sudeep Gupta. Lymphatico-venous communications and rhythmic, respiratory pressure changes influence the incidence of metastatic disease at presentation in solid tumours [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-57.

Background-Traditionally, endocrine therapy follows chemotherapy for hormone receptor (HR) positive breast cancer (BC) in the adjuvant setting. Concurrent chemo-hormonal therapy fell into disrepute due to previous studies showing a probable, small detriment in survival. (Albain et al, Lancet, 2009; Bedognetti et al, JNCI, 2009; Pico et al, Ann Oncol, 2004) However, the early studies are fraught with biases. The biological rationale was that endocrine therapy is cytostatic, pushing cancer cells into G0 phase which was feared to reduce the efficacy of chemotherapy which is known to act best on rapidly dividing cells. Thus, the two mechanisms of actions were thought to be antagonistic. However, this fear may be irrational and evidence at molecular level is contradictory. The current sequential strategy delays the start of an equally effective treatment modality in HR+ BC patients. Recent studies have shown that concurrent chemo-endocrine therapy is safe in metastatic HR+ setting. (Sledge et al, J Clin Oncol, 2000) One also needs to rethink neoadjuvant strategies in these patients to improve the current dismal pathological complete response (pCR) rates in this subset. (Cortazar et al, Lancet, 2014) Concurrent treatment seems to have improved pCR rate. (Sagiu K et al, Acta Med Okayama, 2015) Here, we describe a phase III, randomized study aimed to evaluate the efficacy of concurrent chemo-endocrine therapy in the adjuvant and neoadjuvant setting. (CTRI/2018/09/015643) Aims and Objectives- The primary objective is to assess the improvement in disease-free survival by administering concurrent versus sequential, (neo) adjuvant chemo-endocrine therapy in HR+, HER2 negative, non-metastatic BC. The secondary objectives are to assess improvement in overall survival, pCR rates, breast conservation rates. Biomarkers of response to treatment and tumour dormancy in HR+ BC will be studied in a subset of patients.Patients and methods-This is a prospective, open label study where non-metastatic, biopsy proven, HR+, HER2- BC patients who warrant chemotherapy in the adjuvant or neoadjuvant setting are considered. The study started accrual in December 2018 and 285 patients are randomized till date. Pregnant or lactating women and those with inflammatory breast carcinoma are excluded. After obtaining informed consent, patients are randomized to receive concurrent versus sequential chemo-endocrine treatment. Patients will receive all chemo and endocrine therapy as per the institutional standard protocols otherwise. Stratification criteria are neoadjuvant vs adjuvant therapy, pre vs postmenopausal status, node positive vs node negative status, 1st gen (anthracyclines alone) versus 2nd gen (including taxanes) chemotherapy. A two-sided log-rank test with an overall sample size of 2316 (2432 with a 5% dropout rate) (1158 in control and 1158 in treatment group) achieves 80% power at a 0.05 significance level to detect a hazard ratio of 0.80 when the proportion surviving in the control group is 0.70. An interim with respect to safety is planned in the protocol. Expected results and conclusion-Ours is a large, prospective trial evaluating the efficacy of concurrent chemo-endocrine therapy in HR+ BC patients. This has the potential to improve pCR rates in the neoadjuvant setting and change the standard of care in the management of HR+ BC patients. The biomarker analysis will help us further understand the biology of HR+ BC and shed light upon tumour dormancy signatures. Citation Format: Shalaka Joshi, Sridevi Murali-Nanavati, Vaibhav Vanmali, Rohini Hawaldar, Mujahid Gafur Shaikh, Mohammad Sadique Ansari, Sushmita Rath, Jaya Ghosh, Seema Gulia, Jyoti Bajpayi, Nita Nair, Vani Parmar, Purvi Thakkar, Garvit Chitkara, Tanuja Shet, Sangeeta Desai, Ayushi Sahay, Sudeep Gupta, Rajendra Badwe. Concurrent versus sequential chemo-endocrine therapy in er positive and her2 negative non-metastatic breast cancer- an open-label, phase III, randomized controlled trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-08-01.

Introduction: A positive resection margin after breast conserving treatment (BCT) is one ofmost important risk factor for tumour recurrence. The appropriate negative margin widthpost BCS for both ductal carcinoma in situ (DCIS) and invasive carcinoma (IC) has seen a shifttowards conservation in guidelines. In 2014, consensus guidelines based on a metaanalysis,defined a negative margin as no ink on tumour for IC and 2mm for DCIS.Methodology: We conducted a retrospective audit of patients who underwent BCS at ourinstitute in 2013 and 2016, pre and post change of guidelines and evaluated the impact onrisk of recurrence. We included all cases operated upfront and post neoadjuvantchemotherapy (NACT). Patient demographic, clinicopathological data and follow up datawas obtained from the hospital electronic medical records. Pathological evaluation ofmargins considered negative in 2013 included IDC more than 2 mm and DCIS more than 5mm away, while in 2016 a negative margin was defined as no tumour on ink for IC and morethan 2 mm for DCIS.Results: A total of 1259 women underwent BCS at our institute in 2013 and 2016 with atotal 6.6% (83/1259) margin positivity rate (MPR). In 2013 the MPR was 8.5%(52/610),9.8%(38/388) in upfront BCS (BCS) and 6.3%(14/222) in BCS post NACT (yBCS). In 2016 theMPR was 4.8%(31/649), 5.3%(20/377) in BCS and 4%(11/272) in yBCS In 2016 an additional7.5%(49/649) would qualify as margin positive based on previous guidelines. In the overallcohort the median age was 46 years, median T size 3.1 cm, 11% had microcalcification onmammogram outside the lesion (micro+), 88.24% BIRADS B/C density, 85.9% grade 3, 96.3%IDC, 1.2% ILC,2.5% DCIS and 56.71% lymph node negative cancers. The median follow up ofthis cohort was 65.25 months. The 5 Year local recurrence free survival (LRFS) and diseasefree survival (DFS) was 94.6% (95%CI 92.64-96.669) vs 94.7% (95%CI 92.74-96.66) and 84.9%(95%C 81.96-87.84) vs 81.9 (95%CI 78.70-85.04) for 2013 and 16 respectively (p=NS forboth). On multivariate cox regression analysis factors associated with increased risk of localrecurrence (LR) were surgery done Upfront vs post NACT (HR 3.35, 95% CI 1.76-6.26,p=0.0001) MPR (HR 2.76, 95% CI 1.27-5.98, p= 0.01) and presence of micro+ (HR 2.63, 95%CI 1.38-5.03, p=0.003). Mammogram density, EIC and year of surgery had no impact on LR.While age ( HR 0.98, 95% CI 0.96-0.99 p=0.004), lymph node positive (HR 2.48, 95%CI 1.82-3.37, P< 0.0001), higher grade (HR 2.11, 95% CI 1.18-3.79, p=0.012), MPR (HR 1.73, 95% CI1.03-2.90, p=0.037)and surgery done upfront vs post NACT (HR 2.64, 95%CI 1.88-3.74,p= Citation Format: Sridevi Rishabh Murali-Nanavati, Nita Nair, Rohini Hawaldar, Vani Parmar, Tanuja Shet, Shabina Siddique, Vaibhav Vanmali, Shalaka Joshi, Rajendra Badwe. Impact of change in margin negative guidelines for breast cancer on recurrence rates: Single institution audit [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-17.

Background: Ductal carcinoma in situ (DCIS) identified by screening mammography accounts for 20% of breast cancer diagnoses, and microinvasion (DCIS-M) is found in 5%-10%. There are no defined treatment guidelines for palpable DCIS or DCIS-M. The role of screening mammography is now being questioned across the world and in the developing world with no national screening programs, women with DCIS present with a palpable lump in the breast. We conducted a retrospective audit of women with DCIS treated at our institution to classify palpable DCIS and DCIS-M as distinct clinical stages and emphasize the need for a change in management of ‘palpable DCIS’ Methods: Annually we register approximately 1700 new cases of early breast cancer of which DCIS and DCIS-M constitutes less than 1%. Between 2005-2016 we registered 784 cases of with DCIS, DCIS-M and early invasive cancer with extensive intraductal component (EIC) at our centre. A retrospective analysis of these cases was performed. Results: Of the 784 patients case records reviewed, 113 (14.4%) had Tis, 87 (11.1% of all early cases and 43.5% of DCIS) had T1mic, the rest had invasive cancer with EIC, of which 46 (5.9%) wereT1a, 28(3.6%) were T1b, 146 (18.6%) were T1c and 364 (46.4%) wereT2. The median age at presentation was 48 years, median clinical tumour size was 3cm; 740 (94.4%) presented with palpable breast lumps.At a median follow up of 86 months , the disease free survival was 95.6% for Tis, 96.6% T1mic, 90.5% T1 and 82.7% T2 (p=0.00). On follow up distant recurrences were noted in 5(4.4%) patients with Tis, 3(3.4%) with T1mic, 21(9.5%) with T1 and 63(17.3%) with T2, (p=0.00). Limited use of adjuvant chemotherapy in Tis and T1mic may have contributed to the high distant recurrences in that group. Also palpable Tis,T1mic and T1a had higher percentage of HR negative compared to those with larger invasive tumours. Conclusions: DCIS presenting in palpable lesions poses a clinical dilemma for the use of adjuvant therapy. In our cohort 43.5% of the palpable DCIS showed evidence of microinvasion with high risk of distant recurrence compared to screen detected DCIS. We thus need to reconsider grossing techniques to accurately identify foci of invasion, redefine DCIS-M based on number and size of foci of invasion and explore the possible role of adjuvant chemotherapy in treating large palpable DCIS. ResultsTis (N%)T1mic (N%)T1a (N%)T1b (N%)T1c (N%)T2 (N%)cT >2 cm63 (55.8)68 (78.2)28 (60.9)6 (21.4)1 (0.7)363 (99.7)Palpable lump85 (75.2)81 (93.1)39 (83)28 (100)144 (98.6)363 (99.7)Nipple discharge26 (23)6 (6.8)7 (14.9)0 (0)2 (1.3)1 (0.3)Hormone receptor positive (HR+ve)60 (53.1)18 (20.7)18 (38.3)15 (53.6)92 (63)218 (60.6)HER2neu +ve31 (27.4)41 (47.1)13 (27.7)8 (28.6)27 (18.5)93 (25)Axilla +ve6 (5.3)9 (10.3)9 (19.1)9 (32.1)50 (34.2)184 (50.7) Citation Format: Karishma Kirti, Nita Nair, Tanuja Shet, Rohini Hawaldar, Vani Parmar, Seema Gulia, Shalaka Joshi, Sridevi Murali, Vaibhav Vanmali, Bipin Bandre, Sudeep Gupta, Rajendra Badwe. Reconsidering the management of palpable DCIS - A single institution audit [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-23.

Introduction: As a tertiary referral cancer centre, 20-30 % of patients seen in our breast clinic present after excision of the primary breast tumour without oncological principles maintained and no details on the excision margins. We evaluated the safety of excision biopsy (ExBx) as a diagnostic procedure by comparing the outcomes against patients who underwent definitive surgery after a core biopsy/FNAC (CxBx) for diagnosis. Methods: We performed a retrospective audit of the case charts of women with breast cancer treated at our institution. We included women with operable breast cancer (OBC) who presented post ExBx of the primary tumour and those who were treatment naïve and operated after only a CxBx for diagnosis. Results: Of the 1022 women included in the analysis, 551 underwent ExBx for primary diagnosis and 471 had CxBx prior to definitive breast surgery. The excision biopsy group were younger women (median age 44 years) with smaller tumours (median T size 2.5cm), lower HR ( hormone receptor) positive (58.3%) and less number were Her2+ve (16.7 %). In this group 17% received NACT, with 66.4% undergoing breast conservation surgery (BCS), and 37.6% node positive. While in the core biopsy group, the women were older women (median age 50 years) had larger tumours, median 3 cm, with 71.3% HR positive, 18.3% Her2 +ve, 72.8% underwent breast conservation surgery with 44.6 % node positive At a median follow up of 46 months, there was no difference in four year disease free survival (DFS) between ExBx group (83.8% versus 86.8%) and non-ExBx (HR=1.29,95%CI=0.93-1.79, p=0.13). When matched for T size, 699/1022 (69%) had T2 tumours and DFS in ExBx group was 80.7% in compared to 85.7% in non ExBx group. (HR=1.46, 95%CI=1.0-2.11, p=0.04). On multivariate cox regression, T size (HR=1.45,95%CI=1.02-2.07, p=0.03), HR negative (HR=1.61,95%CI=1.15-2.26,p=0.006), node positivity (HR=1.82,95%CI=1.31-2.53,p Conclusion: ExBx of the primary tumour as a diagnostic procedure not performed with oncological principles prior to definitive surgery has a detrimental impact on survival in women with operable breast cancer. Citation Format: Nita Sukumar Nair, Rohini W Hawaldar, Quarratulain Chougle, Vani Parmar, Vaibhav Vanmali, Shabina Siddique, Ashwini Devade, Aarti Pandey, Shalaka Joshi, Sudeep Gupta, Rajendra A Badwe. Impact of lumpectomy for diagnosis of primary tumor on disease free survival in women with operable breast cancer: An institutional audit [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-25.

Background: Despite several studies, the impact of adding platinum on long-term outcomes in triple-negative breast cancer (TNBC) has not been definitively established. We conducted a single-centre randomized phase III trial to evaluate the efficacy and toxicity of adding platinum to standard neoadjuvant chemotherapy in these patients. Methods: Patients with histopathological diagnosis of TNBC without evidence of distant metastases who were planned to be treated with neoadjuvant chemotherapy (NACT) were randomized to experimental or control arms after stratification by menopausal status (premenopausal or perimenopausal, and postmenopausal) and stage [operable breast cancer (OBC, clinical T1-3, N0-1, M0), and locally advanced breast cancer (LABC, cT4 or N2-3, M0)]. NACT in control arm included paclitaxel 100 mg/m2 once per week for 8 weeks followed by doxorubicin (60 mg/m2) or epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) once every 21 days for 4 cycles while in experimental arm carboplatin (area-under-curve 2) was added once per week for 8 weeks with paclitaxel. After NACT patients received standard surgery for primary tumor and axillary lymph nodes (LN) followed by radiotherapy. The primary endpoint was disease-free survival (DFS) and the secondary endpoints were overall survival (OS), pathological complete response (pCR, absence of invasive cancer from breast and LN), and toxicity. Results: Between April 2010 and January 2020, 720 (355 control, 365 experimental) patients with a median age of 46 (25-69) years [< 50 years, 502 (69.7%), premenopausal 418 (58.2%)], were included in the study, of whom 285 (39.6%) had OBC and 435 (60.4%) had LABC, with a median clinical tumor size of 6.0 (1.2- 20.0) cm. At a median follow-up of 67.6 (18.9-142.2) months, in the experimental and control arms, the 5-year DFS were 70.6% (95% CI 65.7-75.5%) and 64.5% (95% CI 59.4-69.6%), respectively (HR 0.79, 95% CI 0.61-1.02, p=0.073), 5-year OS were 74.0 (95% CI 69.3-78.7%) and 66.7% (95% CI 61.6-71.8%), respectively (HR 0.75, 95% CI 0.57-0.98, p=0.034), and pCR were 55.2% (95% CI 49.7-69.5%) and 41.5% (95% CI 36.2-47.0%), respectively (p=0.0004). In subgroup analyses, the benefit of carboplatin was confined to patient’s < 50 years, with significant interaction between treatment and age. In women < 50 years of age, in experimental versus control arms, 5-year DFS and OS were 74.5% vs 62.3% (p=0.003, interaction p=0.003) and 76.8% vs 65.7% (p=0.003, interaction p=0.004), respectively. Addition of carboplatin had a significant beneficial impact on OS after adjusting for baseline clinical tumor size and age in a Cox model (HR 0.75, 95% CI 0.58-0.98, p=0.038). In experimental and control arms, numbers of patients with any grade >/=3 toxicity were 140 (38.5%) and 107/355 (30.14%), respectively, (p=0.02), grade >/=3 neutropenia were 2/364 (0.55%) and 1/355 (0.28%), respectively, grade >/=3 thrombocytopenia were 1/364 (0.27%) and 0 (0%), respectively, and febrile neutropenia were 26/364 (7.14%%) and 18/355 (5.07%), respectively (p=0.25). Conclusions: This study, to our knowledge the largest reported trial of neoadjuvant platinum in TNBC thus far, suggests that addition of carboplatin to sequential taxane-anthracycline neoadjuvant chemotherapy results in substantial and clinically meaningful improvement in disease-free and overall survival in young patients with TNBC and should be the standard of care in these patients. Citation Format: Sudeep Gupta, Nita S. Nair, Rohini Hawaldar, Vaibhav Vanmali, Vani Parmar, Seema Gulia, Jaya Ghosh, Shalaka Joshi, Rajiv Sarin, Tabassum Wadasadawala, Tejal Panhale, Sangeeta Desai, Tanuja Shet, Asawari Patil, Garvit Chitkara, Sushmita Rath, Jyoti Bajpai, Meenakshi Thakkur, Rajendra Badwe. Addition of platinum to sequential taxane-anthracycline neoadjuvant chemotherapy in patients with triple-negative breast cancer: A phase III randomized controlled trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-01.

Rationale: Surgery results in rapid and progressively severe exposure of tumor tissue to hypoxia, up to the point of complete removal, but its effect on tumor gene expression is not well characterized. We document the molecular effects of surgery on primary breast cancer tumor with a serial tissue sampling strategy, including an intra-operative sample. Methods: We included treatment naïve, non-metastatic breast cancer patients and sampled tumor and tumour adjacent normal tissue during surgery at three time points: beginning of surgery (Sample A), after half the tumor circumference had been devascularized (Sample B) and from completely resected tumor (Sample C). Patients were divided into two groups: discovery and validation. Tumor or adjacent normal samples from the discovery group underwent whole transcriptome paired-end sequencing (RNA-Seq) generating at least 50 million reads using next generation sequencing. Findings from discovery group were evaluated in a validation group using qRT-PCR and Nanostring nCounter gene expression profiling. Results: 81 breast cancer patients were eligible for this study of whom 46 with at least 1 quality passed sample at time-point A, B or C comprised the discovery group whose samples underwent RNA-seq. Validation group comprised two subsets: 35 independent patients (8 patients’ samples qRT-PCR, data included here; 27 patients’ samples nCounter gene expression, data will be presented) and 17 patients from discovery group whose samples also underwent nCounter gene expression profiling (data will be presented). Individual patient based analyses for A vs B vs C in discovery group revealed 249 significantly de-regulated genes in at least 20% of patients, in at least one comparison (AvB or BvC or AvC). Genes involved in stress response (FOSB, FOS, JUN, JUNB, DUSP1, CYR61, EGR1-3, ATF3, RGS1, RGS2), inflammation (IL20, IL8, SOCS3, GABRP, PIGR, NR4A1-2, CCL2- 3, CCL21, CCL14, CCL18-19, CXCL2, CXCL9-10, CXCL14), invasion & migration (PTGS2, MMP9-13), lipid metabolism (CD36, LIPE, TAT, FABP4, PLIN1, PLIN4, LPL, LEP), epithelial markers (KRT5, KRT7, KRT14-17, KRT23, KRT6A-6B) and cellular differentiation(SOX10, LRP2, S100A2, S100A7-A9, S100B, S100P) were significantly deregulated at time-point B versus A and many of these genes were also significantly deregulated in C versus A comparison, suggesting sustained deregulation through surgical resection. Replicative analysis involving comparison of tumors grouped by time points (A vs B vs C) identified 192 genes uniquely de-regulated in any one of the 3 comparisons, of which 42 overlapped with patient-wise analysis. These 42 genes included all the AP-1 transcription factor network signaling genes, epithelial markers (KRT14, KRT6A), inflammation related genes (SOCS3, PIGR, GABRP, NR4A1, NR4A2), lipid metabolism related genes (PLIN1) and cellular differentiation & cell fate related genes (SOX10, LRP2). Pathway analyses will be presented. qRT-PCR on paired samples in 8 independent patients validated the differential expression of eight genes in either AvB or AvC or both comparisons: FOS, FOSB, JUNB, DUSP1, RGS1, NR4A2, ZFP36, andMMP13. Comparison of biopsy (corresponding to A) with surgical samples (corresponding to C) in 6 cancer types (breast, cervical, lymphoma, mesothelioma, esophageal and sarcoma) in TCGA studies showed statistically significant de-regulation of 11 AP-1 transcription factor network signaling related genes in at least 4 cancers, further validating our experimental results. Conclusions: Our experiment, uniquely including an intra-operative tumor sample, shows that surgical removal induces a conserved stress response in the primary tumor that is potentially capable of bestowing metastatic capability on the tumor cells. Citation Format: Sudeep Gupta, Rohan Chaubal, Nilesh Gardi, Sunil Pachakar, Dimple Bhatia, Poonam Gera, Nita Nair, Shalaka Joshi, Vani Parmar, Purvi Thakkar, Garvit Chitkara, Rasika Kadam, Sejal Gujarathi, Harsh Oza, Rohini Hawaldar, Vaibhav Vanmali, Kenneth Buetow, Amit Dutt, Rajendra Badwe. Molecular effects of surgical resection on primary breast tumor [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-01.

Introduction: Several online prediction models that use known prognostic factors in breast cancer (BC) are routinely used to assist in decisions regarding overall survival (OS) benefit of adjuvant systemic therapy. PREDICT ver 2.2 (P2.2) is one such freely available online tool, which uses T size, LN positive, grade, age, hormone receptor (HR), HER2neu status and Ki67.We performed an external validation of P2.2 for overall survival in a retrospective cohort of patients with non-metastatic invasive breast cancer treated at a single tertiary care centre in India. Methodology: Women treated for operable BC (OBC) between 2008 and 2016 with non-metastatic, T1-T2 invasive, HER2neu receptor negative BC and with available 5-year OS data were selected for this study. Median predicted 5- year OS rates were used to calculate predicted events for the whole validation cohort and subgroups. Chi-squared test was used to evaluate the goodness- of-fit of the tool. Results: A total of 2780 eligible patients were included in the analysis with median age of 50(25-82) years, median pT size of 2.5 (0.1-5) cm, 2006 (72.2%) having grade 3 tumour, 1190(42.8 %) having node-positive disease and 883 (31.8%) having triple negative breast cancer(TNBC). The observed and predicted 5-year OS in the whole cohort were 93.74% (95% CI92.77-94.58) and 89.00% (95% CI 89-90), respectively, with an absolute difference of 4.74%(95% CI 3.27-6.22, p 2 cm (92.82%, 95%CI 91.69-93.88, versus 87%, 95%CI 86-88, p Citation Format: Bhavika Kothari, Nita Nair, Sadhana Kannan, Rohini Hawaldar, Vani Parmar, Shabina Siddique, Vaibhav Vanmali, Ashutosh Tondare, Garvit Chitkara, Purvi Thakkar, Tanuja Shet, Shalaka Joshi, Rajendra Badwe. Validation of PREDICT version 2.2 on a retrospective cohort of Indian women with operable breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-05-14.

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.

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 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.

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.

7033 Background: Shared decision making to confront choices with clinical equipoise, has been the privilege of those patients with access to time intensive consults with oncologists. We conducted a randomized controlled trial for breast cancer patients to use an online, self-administered, out-of-the-medical-encounter decision aid (DA) to choose between breast conserving surgery (BCS) and mastectomy. Methods: Navya Patient Preference Tool (Navya PPT) is a multilingual DA based on adaptive conjoint analysis of tradeoffs between cost, adverse effects of radiation, and breast conservation. Prior analysis established high internal reliability and external validity of the Navya PPT. Eligible cT1/2, cN0 breast cancer patients planned for surgery were block randomized, in 1:1:1 ratio, to receive the research questionnaire (RQ) to measure decisional conflict on choice of surgery (control, arm 1), Navya PPT followed by RQ (experimental, arm 2) or Navya PPT followed by RQ administered with key male family member (experimental, arm 3). Groups were stratified with respect to age, socio-economic status (SES) and educational level. The study was powered to detect a decrease in Decisional Conflict Index (DCI) by 0.25 (β-0.8, two sided α- 0.01). Results: Between June 2017 and December 2019, 247/255 patients were randomized to arm 1 (83), arm 2 (84), and arm 3 (80). Median age was 48 years (IQR 23-76), and median pT size was .5 cm (0.5-6 cm). 59% of patients were middle or lower SES and 46.2% had ≤ 12th grade education. DCI was significantly reduced in arm 2 as compared with arm 1 (1.34 vs. 1.65, Cohen’s d 0.49 (± 0.31) p

Introduction: Access to expert, evidence based clinical decision making is crucial in maximizing the outcome of women with breast cancer, but is a scarce resource, especially in developing countries. The Navya Expert System is a patented, software based clinical decision support system that exhaustively searches and assimilates relevant medical literature and guidelines to make specific therapeutic recommendations for individual patients based on their clinical data. This study is a retrospective validation of Navya Expert System's output against tumor board decisions of a multidisciplinary group of expert breast cancer clinicians working in a tertiary care oncology center in India. Methods: Women with non-metastatic breast cancer who had already completed their loco-regional and systemic therapy based on the recommendations of the tumor board were included in the study. The protocol specified clinical and pathology data of these women were retrospectively abstracted from their case charts and processed through the Navya Expert System. The output was classified into major (neo-adjuvant chemotherapy versus upfront surgery and need for adjuvant chemotherapy, endocrine therapy and radiation therapy, respectively) and minor (breast conservation versus mastectomy, taxane versus non-taxane adjuvant chemotherapy and need for nodal radiation therapy) therapeutic decisions. Decisions discordant between the tumor board and the Navya Expert System were adjudicated by an expert panel of breast cancer clinicians from the same institution. Navya Expert System decisions were classified as discordant with appropriate clinical practice if they were in disagreement with both the tumor board and expert panel. All other Navya Expert System decisions were classified as concordant. The primary outcome of the study was concordance between the Navya Expert System and the tumor board or expert panel for major and minor therapeutic decisions. Results: A total of 76 patients involving 224 major and 224 minor therapeutic decisions were included in the study. Navya Expert System's output was concordant with the tumor board or expert review in 224/224 major decisions (100%, 95% CI 99.6%-100%) and 221/224 minor decisions (98.6%, 95% CI 97.1%-100%). Navya Expert System's output was concordant with the tumor board alone in 210/224 (93.75%, 95% CI 90.6%-96.9%) major decisions and 160/224 (71.4%, 95% CI 65.5%-77.3%) minor decisions. Most common reasons for discordance were non-prescription of HER2 targeted therapy by the tumor board due to financial constraints and non-use of nodal radiation for 1-3 node positive patients. Of the 64/224 Navya Expert System decisions discordant with the tumor board, only 3 were finally deemed discordant after review by the expert panel. Conclusions: Navya Expert System treatment recommendations, only requiring the input of commonly available clinical data, are highly concordant with those of a tumor board comprised of breast cancer experts with high level expertise. If these results can be prospectively validated, Navya Expert System has the potential to increase global access to evidence based clinical decision making in breast cancer. Citation Format: Nita Nair, Sudeep Gupta, Naresh Ramarajan, Gitika Srivastava, Vani Parmar, Anusheel Munshi, Shraddha Vanmali, Vaibhav Vanmali, Rohini Hawaldar, Rajendra A Badwe. Validation of a software based clinical decision support system for breast cancer treatment in a tertiary care cancer center in India [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-16-01.

Background Sentinel node biopsy (SNB) was initially conceived as excision of the first station axillary lymph node(s) (LN) identified by radioactive and/or blue dye uptake. The definition was subsequently enlarged to also include palpable lymph nodes in the vicinity of sentinel node(s) (SN). We reasoned that the excision of this combination of nodes might be best achieved by sampling the lower axilla. Methods Each patient underwent low axillary sampling (LAS) and identification of SN in the excised specimen followed by complete axillary lymph node dissection (ALND). LAS was defined as excision of all fibrofatty tissue overlying the second digitation of serratus anterior below the intercostobrachial nerve and was carried out following a pre-operative injection of radioactive colloid and an intra-operative injection of blue dye. Blue and/or hot nodes (B&/HN) in the dissected tissue and remaining axilla, along with any palpable nodes within the sampled tissue, were defined as SN. The primary endpoint of the study was to compare false negative rates (FNR) of SN with that of LAS in predicting axillary LN status (NCT00128362). Findings The study was performed between March 2004 and December 2011 in 478 women with clinically node negative axilla. On histopathological evaluation the median tumor size was 2.5 cm and axillary nodal metastases were found in 34.1% of patients. The FNR of SNB (12.7%, 95% CI 8.1–19.4) and LAS (10.5%, 95% CI 6.6–16.2) were not significantly different ( p = 0.56). The FNR of B&/HN alone, without palpable nodes, (29.0%, 95% CI 22.5–36.6) was significantly inferior to those of SNB ( p = 0.0007) and LAS ( p = 0.0003). Interpretation LAS is as accurate as SNB in predicting axillary LN status in women with clinically node negative operable breast cancer. Confining SNB procedure to excision of B&/HN, significantly increases the risk of leaving behind metastatic lymph nodes in the axilla. LAS is an effective and low cost procedure that minimizes axillary surgery and can be implemented widely. Registry Name : Clinicaltrials.gov. Registration Number : NCT00128362.

Survival studies may serve as benchmarks to develop cancer-related policies and estimate baseline survival rates in a given patient population.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.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%, P0.001. The factors adversely affecting DFS in EBC were node metastasis (P0.001), higher metastatic nodes (P0.001), 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, P0.001) 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 (P0.001), increasing numbers of nodes (P0.001), presence of lymphovascular emboli (LVE) (P0.01), mastectomy (P0.001), and Her2neu positivity (P = 0.03). In the multivariate Cox regression analysis, node positivity (HR 2.96, 95% CI 2.04-4.29, P0.0001), 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.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.

Background: Hypoxia is defined as oxygen levels in tumor microenvironment of less than that in blood (90-100 mm Hg) and influences many aspects of tumour biology. During surgery tumour vasculature is cut off gradually leading to induction of acute hypoxia.The present study aims to experimentally test the genotypic and phenotypic effects of surgically induced acute hypoxia in breast cancer tumor samples and cell lines. Methodology: Core biopsy samples were collected from breast tumors (N=8 patients) at three time points during their curative surgery: prior (pre), mid-way (intra) and at the end (post). The samples were subjected to RNA-Seq and a list of differentially expressed genes (DEG) was prepared. A set of 26 DEG (‘pre’ Vs ‘intra’ Vs ‘post’) obtained from RNA-Seq analysis and additional 17 genes involved in inflammation, EMT and hypoxia pathways were chosen for validation in tumor samples. These genes were validated using a customized qPCR Array (Qiagen). A gene was considered validated if it was significantly deregulated in at least 4 out of 8 patients. In another experiment, MCF-7 cells were exposed to varying levels of oxygen concentrations (0.1-20%) for varying time periods ranging from 30 minutes to 72 hours, to study time and dose dependent effects of hypoxia on following functional characteristics: proliferation, invasion and cell cycle changes. Results: Concordant, statistically significant up-regulation of FOS, DUSP1, JUNB, FOSB, ZFP36, RGS1, S100A4, CXCL8 and CCL2 were observed in RNA-Seq and qPCR experiments while MMP13, HIF1A and VEGFA were up-regulated only in qPCR. However, 7 protein markers of inflammation, EMT and hypoxia did not show any significant change between pre, intra and post-operative samples. In MCF-7 cells, a dose and time dependent decrease in cell viability was observed with increasing severity of hypoxia as well as decrease in invasiveness, but there was no significant impact on cell cycle phases. When hypoxic cells were re-incubated under normoxic conditions an increase in cell proliferation and accumulation of cells in S phase (with a reduction in G2-M fraction) were observed, compared to cells grown under only normoxic conditions. Conclusion: Acute intra-operative hypoxia up-regulates expression of genes related to cell survival, chemoresistance, invasiveness, inflammation and angiogenesis in breast tumors. Breast cancer cells exposed to acute severe hypoxia followed by normoxia show increased proliferation. These effects may have implications for tumor cells that disseminate during surgery. Citation Format: Dimple R. Bhatia, Shalaka Joshi, Rohan Chaubal, Poonam Gera, Prajakta Kalkar, Farheen Naeem, Nisanth Mathew Raju, Nilesh Gardi, Nita Nair, Vaibhav Vanmali, Rohini W. Hawaldar, Amit Dutt, Rajendra A. Badwe, Sudeep Gupta. The effect of acute intraoperative hypoxia in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4524. doi:10.1158/1538-7445.AM2017-4524

e11552 Background: Paclitaxel is an integral component of chemotherapy for breast cancer but its benefit comes at the risk of peripheral neuropathy. There are experimental models of peripheral nerve injury in which progesterone is protective, possibly through remyelination and other mechanisms. Methods: We evaluated the effect of menopausal status, as a surrogate for circulating progesterone levels, on the risk of developing paclitaxel induced peripheral neuropathy, in a retrospective audit of breast cancer patients. Patients who had received paclitaxel chemotherapy for breast cancer were characterized as having CIPN or not by clinical history/examination. Results: 256 women treated with paclitaxel at our institution were assessed for CIPN. Of these 133(52%) were premenopausal and 123(48%) postmenopausal at diagnosis. 22(8.6%) had preexisting diabetes mellitus. Of the 133 premenopausal women 97(72.9%) developed chemotherapy induced amenorrhea (CIA). The incidence of CIPN was 23.1% in persistently premenopausal patients 47.4% in patients with CIA and 57.7% in postmenopausal patients. In patients with DM 81.8% had CIPN. In a multivariate logistic regression model, increasing age (continuous variable RR=1.04 95%CI 1.02-1.08 p=0.001) DM (RR=4.39 95% CI 1.42-13.38 p=0.01) and postmenopausal/CIA status (RR=2.48 95% CI 1.05-5.88 p=0.03) were risk factors for CIPN. Because patients developed CIA at variable times and circulating progesterone levels at the time of neurotoxin insult maybe variable in them such patients were excluded in the second model, which included only patients with continuing menses (n=36) and postmenopausal at diagnosis (n=123). In the latter model postmenopausal status (RR=3.5 95%CI 1.18-10.39 p=0.02) and DM (RR=6.8 95%CI 1.44-31.82 p=0.01) were associated with CIPN but increasing age (RR=1.03 95% CI 0.98-1.07 p=0.21) was not. Conclusions: These results suggest a neuroprotective effect of premenopausal status, possibly related to higher circulating levels of progesterone. We hypothesize that progesterone administration prior to taxane chemotherapy may protect against CIPN. This will be tested in a RCT.

1108 Background: Post neoadjuvant chemotherapy (NACT) sentinel node biopsy (SNB) is not a standard of care due to the wide variability in false negative rate (FNR), varying from 5.7% to 33%. In operable breast cancer (OBC), FNR of less than 10% is acceptable. We attempted to find out the reliability of low axillary sampling(LAS), with dissection limited below the first intercostobrachial nerve, to correctly identify the node negative axilla in the post NACT clinically node negative (N0) patients. Methods: Women with large operable (LOBC) and locally advanced breast cancer (LABC), post-NACT clinically N0, underwent concomitant blue dye-colloid guided SNB and LAS. The identification rate, FNR, and negative predictive value (NPV) of both procedures were compared. Results: Post-NACT 209 eligible women underwent combined LAS and SNB procedure. At presentation, the tumors were large (median 5.0 cm) with 70% clinically palpable nodes. All patients received 4 cycles of neo-adjuvant anthracycline-based chemotherapy and were clinically node negative after chemotherapy. SNB was defined as blue and/or hot node plus palpable node(s). A blue or hot node (median 2 nodes) was identified in 93.8%, and median of 5 sentinel nodes were removed. The false negative rate of SNB was 15.3% (95% CI 8.7%-25.3%). The LAS technique comparatively had nodal yield in 98.5% with median 8 nodes removed; and FNR 8.5% (95% CI, 4.2%-16.6%, p=0.19). Comparative NPV for LAS and SNB were 94.6% and 91.8% respectively. Conclusions: Axillary sampling results for FNR and NPV are similar if not superior to SNB and could be a reliable method of axillary nodal evaluation in advanced breast cancers following neo-adjuvant chemotherapy.

146 Background: Ductal carcinoma in situ (DCIS) identified by screening mammography accounts for 20% of breast cancer diagnoses, and microinvasion (DCIS-M) is found in 5%-10%. There are no defined treatment guidelines for palpable DCIS or DCIS-M. In the developing world wherein screening mammography is controversial due to a predominantly premenopausal population, most women with DCIS present with a palpable lump in the breast. The objective of this study was to evaluate whether disease in these patients with palpable DCIS have been treated differently from screen detected DCIS. Methods: Annually we register 3,000 new cases of breast cancer of which DCIS constitute a small fraction. Over a period of 12 years (1998-2010) we registered 71 cases of DCIS for treatment. A retrospective analysis of these was performed. Results: Of the 71 patients reviewed, 35 (49.2%) had foci of microinvasion. The median age of presentation was 49 years and mean tumor size was 2.3 cm; all presented with palpable breast lumps. Of the 36 women with DCIS alone Tsize was > 2 cm in 26 (72.2%), 14 (38.9%) had presence of comedo necrosis and 1 (2.7%) had positive lymph nodes on histopathology. Adjuvant chemotherapy was given to 4 (11.11%). Of the 35 women with DCIS-M Tsize was > 2 cm in 23 (66%), 10 (29%) had comedo necrosis (compared to 38.9% in pure DCIS p=0.45), 3 (8.5%) had positive lymph nodes, and 17 (48.6%) received chemotherapy. We compared this data to that of women treated for invasive ductal carcinoma with pTsize Conclusions: DCIS presenting in these palpable lesions poses a clinical dilemma for the use of adjuvant therapy. Over 49.2% of the palpable DCIS showed evidence of microinvasion. We thus need to consider the role of adjuvant chemotherapy when treating women with palpable DCIS.