Rajan Badwe

Abstract S2-02: Surgical removal of primary tumor and axillary lymph nodes in women with metastatic breast cancer at first presentation: A randomized controlled trial

BACKGROUND: The role of loco-regional treatment, in women with metastatic breast cancer (MBC) at first presentation, is debatable. Preclinical evidence suggests that such treatment may facilitate growth of metastatic disease. On the other hand, many retrospective analyses in clinical cohorts have suggested favorable impact of loco-regional treatment in these patients. However, these results are likely to be influenced by selection bias. We conducted a prospective randomized controlled trial to assess the impact of loco-regional treatment on outcome in women with metastatic breast cancer at initial diagnosis. [NCT00193778] METHODS: Women with metastatic breast cancer at initial diagnosis and planned to be treated with anthracycline based chemotherapy (CT) were registered for the study. Those who had objective tumor response after 6 cycles of CT were randomized to one of the following arms: ‘LRT’ (loco-regional treatment) or ‘No-LRT’ (no loco-regional treatment). Patients were stratified by endocrine receptor (ER) status, site of metastases (visceral Vs bone Vs both) and number of metastatic lesions ( 3). Women in LRT arm received surgery (breast conservation or mastectomy plus axillary lymph node dissection) followed by radiation therapy (RT), as per standard adjuvant guidelines. Women in No-LRT arm were followed up without surgery and RT. Both groups received standard endocrine therapy after last cycle of chemotherapy, if indicated. They were regularly followed up with clinical evaluation. Appropriate imaging was performed within 6 months after randomization and thereafter as clinically indicated. The primary endpoint was overall survival (OS). RESULTS: Between Feb 2005 and Jan 2013, 350 women were randomized, 173 in LRT and 177 in No-LRT arm. The data cutoff was in May 2013. The two arms were balanced with respect to age, clinical tumor size, HER2 receptor status and stratification factors. Eight (5.8%) patients in the LRT arm did not undergo loco-regional therapy while 19 (10.7%) patients in the No-LRT arm underwent surgical removal of primary tumor because of palliative reasons. The median follow-up was 17 months and 218 deaths (LRT = 111/173, No-LRT = 107/177) had been recorded at data cutoff. The median OS in LRT and No-LRT arms were 18.8 and 20.5 months (HR = 1.07, 95%CI = 0.82-1.40, p = 0.60) and the corresponding 2-year OS were 40.8% and 43.3%, respectively. After adjusting for age, ER status, HER2 receptor status, site of metastases and number of metastatic lesions in a Cox regression model, there was no significant difference in OS between LRT and No-LRT arms (HR = 1.00, 95%CI = 0.76-1.33, p = 0.98). There was no interaction between the effect of LRT and covariates in the model. CONCLUSIONS: Loco-regional treatment of the primary tumor and axillary nodes has no impact on OS in patients diagnosed with MBC at initial presentation, who have responded to frontline chemotherapy. We were unable to identify any subgroups that are likely to benefit from LRT. Such treatment should be reserved for women who need it for palliative reasons. Detailed analysis will be presented at the Symposium. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S2-02.

Changes in the Tumor Grade and Biological Markers in Locally Advanced Breast Cancer after Chemotherapy – Implications for a Pathologist

Abstract:  There is insurgence of literature evaluating prognostic and predictive factors in breast carcinomas treated with chemotherapy, with a parallel need to develop guidelines for the pathologist interpreting such excisions. Prechemotherapy gun biopsy and postchemotherapy excision specimens from 78 women with locally advanced breast cancer were analyzed for histological changes in the tumor, changes in the tumor grade, hormone receptors, cerb2, and bcl2 and their impact on disease‐free survival (DFS). An unusually prominent granulomatous response to tumor was seen in three cases. The tumor grade changed in five patients, estrogen receptor (ER) expression was altered in 10 cases, progesterone receptor detection changed in 16 cases, cerb2 in one case and bcl2 in 16 cases. Fixation of the gun biopsy in Bouin’s fluid and severe damage of nuclei after chemotherapy were the reasons for shift in the expression of hormone receptors. A low‐grade tumor was associated with better response to chemotherapy. In the Kaplan–Meier analysis the ER expression and a low‐grade tumor (grade I and II) significantly affected DFS. None of the factors evaluated impacted the overall survival of patients. To conclude there is a change in the tumor grade, bcl2, cerb2 and hormone receptors after chemotherapy. A pathologist interpreting specimens of breast cancer after chemotherapy must always record the postchemotherapy grade as it is an indicator of better response to chemotherapy and survival.

Role of adhesion molecules in recruitment of Vδ1 T cells from the peripheral blood to the tumor tissue of esophageal cancer patients

Abstract The mechanism responsible for tissue specific localization of γδ T cell subsets is not well understood. In order to explain the sequestration of specific γδ T cell subsets in the peripheral blood and tumor tissue of patients with esophageal cancer, we examined the function and expression of adhesion molecules on these cells. A hierarchy in the expression of adhesion molecules was observed. In vitro activated γδ T cells showed dominant expression of LFA-1 (CD11a), VLA-α4 (CD49d), intermediate expression of VLA-α5 (CD49e) and L-selectin (CD62L), but low expression of CD44v6 and αEβ7 (CD103). It was observed that the γδ T cells use LFA-1, L-selectin and CD44v6 to bind to squamous cell carcinoma (SCC) cells, whereas they adhere to fibroblast cells using LFA-1, VLA-α4 and VLA-α5. Vδ1 T cell subsets from the peripheral blood γδ T cells utilize a larger array of adhesion molecules, namely LFA-1, VLA-α4, VLA-α5, L-selectin and αEβ7, to bind to SCC cells compared to the restricted usage of LFA-1, L-selectin and CD44v6 by the Vδ2 T cells. Flow cytometric analysis of tumor infiltrating lymphocytes from the esophageal tumors confirmed the selective accumulation of Vδ1+γδ T cells in the tumor compartment. It thus appears that adhesion molecules expressed on these lymphocytes play an important role in the recruitment and retention of Vδ1 T cells in the tumor milieu.

Increase in breast cancer incidence among older women in Mumbai: 30-Year trends and predictions to 2025

BACKGROUND Increasing trends in the incidence of breast cancer have been observed in India, including Mumbai. These have likely stemmed from an increasing adoption of lifestyle factors more akin to those commonly observed in westernized countries. Analyses of breast cancer trends and corresponding estimation of the future burden are necessary to better plan rationale cancer control programmes within the country. METHODS We used data from the population-based Mumbai Cancer Registry to study time trends in breast cancer incidence rates 1976-2005 and stratified them according to younger (25-49) and older age group (50-74). Age-period-cohort models were fitted and the net drift used as a measure of the estimated annual percentage change (EAPC). Age-period-cohort models and population projections were used to predict the age-adjusted rates and number of breast cancer cases circa 2025. RESULTS Breast cancer incidence increased significantly among older women over three decades (EAPC = 1.6%; 95% CI 1.1-2.0), while lesser but significant 1% increase in incidence among younger women was observed (EAPC = 1.0; 95% CI 0.2-1.8). Non-linear period and cohort effects were observed; a trends-based model predicted a close-to-doubling of incident cases by 2025 from 1300 mean cases per annum in 2001-2005 to over 2500 cases in 2021-2025. CONCLUSIONS The incidence of breast cancer has increased in Mumbai during last two to three decades, with increases greater among older women. The number of breast cancer cases is predicted to double to over 2500 cases, the vast majority affecting older women.

Central obesity increases risk of breast cancer irrespective of menopausal and hormonal receptor status in women of South Asian Ethnicity

Background Current evidence suggests that the relationship between obesity and breast cancer (BC) risk may vary between ethnic groups. Methods A total of 1633 BC cases and 1504 controls were enrolled in hospital-based case–control study in Mumbai, India, from 2009 to 2013. Along with detailed questionnaire, we collected anthropometric measurements on all participants. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence interval (CI) for BC risk associated with anthropometry measurements, stratified on tumour subtype and menopausal status. Results Waist-to-hip ratio (WHR) of ≥0.95 was strongly associated with risk of BC compared to WHR ≤0.84 in both premenopausal (OR = 4.3; 95% CI: 2.9–6.3) and postmenopausal women (OR = 3.4; 95% CI: 2.4–4.8) after adjustment for body mass index (BMI). Premenopausal women with a BMI ≥30 were at lower risk compared to women with normal BMI (OR = 0.5; 95% CI: 0.4–0.8). A similar protective effect was observed in women who were postmenopausal for <10 years (OR = 0.6; 95% CI: 0.4–0.9) but not in women who were postmenopausal for ≥10 years (OR = 1.8; 95% CI: 1.1–3.3). Overweight and obese women (BMI: 25–29.9 and ≥ 30 kg/m2, respectively) were at increased BC risk irrespective of menopausal status if their WHR ≥0.95. Central obesity (measured in terms of WC and WHR) increased the risk of both premenopausal and postmenopausal BCs irrespective of hormone receptor (HR) status. Conclusions Central obesity appears to be a key risk factor for BC irrespective of menopausal or HR status in Indian women with no history of hormone replacement therapy.

Immunocytochemistry on Scrape Cytology in Breast Cancer

Objective To standardize the technique of immunocytochemical (ICC) assessment of estrogen (ER) and progesterone receptor (PR) status in breast cancer by scrape cytology and to compare the results with immunohistochemistry on paraffin blocks. Study Design ICC assessment for ER and PR was done on scrape smears from tissue samples in 200 cases of primary breast cancer. The results were compared to those obtained from immunohistochemical (IHC) evaluation of formalin-fixed paraffin sections obtained from the same tissue samples. Results ER/PR positivity rates as well as staining scores were compared between the scrape smears and tissue sections. The concordance between cytology and histology was 84% for ER and 90% for PR. Both the positivity rates and the staining intensity scores were higher for cytochemistry than for histochemistry. Conclusion The ICC method on scrape smears is a simple test with rapid turnaround time. The sample required is sm,all, and antigen loss due to fixation and processing is minimal. This new method gives a higher yield of hormone receptor positivity and, when used in conjunction with the IHC method, may improve the pickup rate of ER-positive cases, thereby playing an important role in risk stratification and therapeutic decision making in patients with breast cancer.

Fibromatosis-like carcinoma-an unusual phenotype of a metaplastic breast tumor associated with a micropapilloma

BackgroundFibromatosis-like metaplastic carcinoma is a newly described metaplastic breast tumor, literature on which is still evolving.Case presentationA 77-year-old lady presented with a 2 × 2 cm mass with irregular margins in the upper and outer quadrant of left breast. Fine needle aspiration cytology (FNAC) from the lump was inconclusive. A lumpectomy was performed and sent for frozen section, which revealed presence of spindle cells showing mild atypia in a sclerotic stroma. The tumor cells revealed prominent infiltration into the adjacent fat. A differential diagnosis of a low-grade sarcoma vs. a metaplastic carcinoma, favoring the former, was offered. Final histology sections revealed an infiltrating tumor with predominant spindle cells in a collagenous background, simulating a fibromatosis. Adjacent to the tumor were foci of benign ductal hyperplasia and a micropapilloma. Immunohistochemistry (IHC) showed diffuse co-expression of epithelial markers i.e. cytokeratins (CK, HMWCK, CK7) and EMA along with a mesenchymal marker i.e. vimentin in the tumor cells. Myoepithelial markers (SMA and p63) showed focal positivity. A diagnosis of a low-grade fibromatosis-like carcinoma breast associated with a micropapilloma was formed.ConclusionFibromatosis-like carcinoma is a rare form of a metaplastic breast tumor. This diagnosis requires an index of suspicion while dealing with spindle cell breast tumors. The importance of making this diagnosis to facilitate an intra operative surgical planning is marred by diagnostic difficulties. In such cases, IHC is imperative in forming an objective diagnosis.

Place of birth and risk of gallbladder cancer in India

CONTEXT Within India, the incidence of gallbladder cancer (GBC) is characterized by marked geographical variation; however, the reasons for these differences are unclear. AIMS To evaluate the role of place of birth, length of residence, and effect of migration from high- to low-risk region on GBC development. SETTINGS AND DESIGN Population-based cancer registries (PBCRs); case-control study. SUBJECTS AND METHODS Data of PBCRs were used to demonstrate geographical variation in GBC incidence rates. A case-control study data examined the role of birth place, residence length, and effect of migration in etiology of GBC. STATISTICAL ANALYSIS Rate ratios for different PBCRs were estimated using Chennai Cancer Registry as the reference population. Odds ratios (ORs) for developing GBC in a high-risk region compared to a low-risk region and associated 95% confidence interval (CI) were estimated through unconditional logistic regression models using case-control study. RESULTS GBC shows marked variation in incidence with risk highest in Northeast regions and lowest in South India. OR of 4.82 (95% CI: 3.87-5.99) was observed for developing GBC for individuals born in a high-risk region compared to those born in a low-risk region after adjusting for confounders. A dose-response relationship with increased risk with increased length of residence in a high-risk region was observed (OR lifetime 5.58 [95% CI: 4.42-7.05]; Ptrend ≤ 0.001). The risk persisted even if study participant migrated from high- to low-risk region (OR = 1.36; 95% CI: 1.02-1.82). CONCLUSIONS The present study signifies the importance of place of birth, length of stay, and effect of migration from high- to low-risk region in the development of GBC. The data indicate role of environmental and genetic factors in etiology of disease.

Breast conservation in locally advanced breast cancer.

Absence of breast cancer screening in India, lack of awareness in rural population, social inhibitions and poor socioeconomic status leads to a situation where a large proportion of women in India are still presenting with locally advanced breast cancer (LABC) at the time of initial diagnosis, although, there are relatively more of early stage cases detected in the metros and urban areas than maybe a decade ago. With advances in care and introduction of newer chemotherapeutic agents, it has now become feasible to offer neoadjuvant therapy with effective tumor downsizing, thus making it possible to even consider breast conservation surgery in select patients with locally advanced and unresectable disease at presentation. With reports suggesting apparent safety of the procedure, breast conservation treatment after chemotherapy is now being offered as routine care in most major centers for selective women with LABC. Multimodality therapy is the standard of care with neoadjuvant systemic therapy for all women with LABC.

A Prospective Study of Computerized Digital Infrared Image Analysis (NoTouch BreastScanTM) in Biopsy Proven Breast Cancers.

Introduction: Early detection of breast cancer is known to have a more favourable outcome. Currently clinical breast examination and imaging modalities, primarily mammography are used for screening purposes. In India, more than 85% of the population is below the age of 50 years, wherein the sensitivity of mammography is at best 64%. Additional drawbacks of the procedure are physical discomfort and ionizing radiation dose to the patient. So newer techniques have been investigated which detect cancer induced neovascularity with digital thermal imaging. The purpose of this clinical study was to determine the efficacy of a software assisted thermal image analysis tool to distinguish between benign and malignant lesions of the breast.Methods: A prospective study was conducted in women who presented to the breast clinic with clinically or mammographically suspicious breast lesions. They also underwent thermal imaging of the breast. All mammographically suspicious lumps were subjected to histopathological confirmation. The mammography and infrared (IR) reports were compared to the histopathology.Results: In 90 women, 180 breasts were independently analyzed by both digital IR software analysis and mammography. Eighty five out of these 180 had suspicious lesions on mammography or clinical examination which were subjected to pathological confirmation. Mammography being the present diagnostic gold standard, all normal mammograms in clinically normal breast were considered as non-malignant. The sensitivity and specificity of digital thermography in detecting malignant lesions was 88.24% and 70.52% respectively with NPV of 87.01% and PPV of 72.82%. While for mammography the sensitivity and specificity were 96.25% and 96.7% with NPV of 96.7% and PPV of 96.25%. In women below 50 years of age (62/90) the sensitivity and specificity of digital thermography was 89.83% and 64.61% with NPV of 87.5% and PPV of 69.74%. Further, in the same subset no statistically significant difference was detected in the sensitivity of digital thermography to that of mammography (p = 0.7263).Conclusion: Our initial experience shows that the detection rate by digital thermal imaging is comparable to mammography in clinically palpable breast tumors. We also note that there is no significant difference in sensitivity of thermal imaging in women on either side of 50 making it a potentially testable tool for screening in younger women. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5028.