Vani Parmar

Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials

BACKGROUND The combined efficacy analysis of the TEXT and SOFT trials showed a significant disease-free survival benefit with exemestane plus ovarian function suppression (OFS) compared with tamoxifen plus OFS. We present patient-reported outcomes from these trials. METHODS Between Nov 7, 2003, and April 7, 2011, 4717 premenopausal women with hormone-receptor positive breast cancer were enrolled in TEXT or SOFT to receive unmasked adjuvant treatment with 5 years of exemestane plus OFS or tamoxifen plus OFS. Gonadotropin-releasing hormone analogue triptorelin, bilateral oophorectomy, or bilateral ovarian irradiation were used to achieve OFS. Chemotherapy use was optional. Randomisation with permuted blocks was done with the International Breast Cancer Study Groups internet-based system and was stratified by chemotherapy use and status of lymph nodes. Patients completed a quality of life (QoL) form comprising several global and symptom indicators at baseline, every 6 months for 24 months, and then every year during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6 months, 24 months, and 60 months with mixed-models for repeated measures for each trial with and without chemotherapy and overall. The analysis was by intention to treat. At the time of analysis, the median follow-up was 5·7 years (IQR 3·7-6·9); treatment and follow-up of patients continue. The trials are registered with ClinicalTrials.gov, as NCT00066703 (TEXT) and NCT00066690 (SOFT). FINDINGS Patients on tamoxifen plus OFS were more affected by hot flushes and sweats over 5 years than were those on exemestane plus OFS, although these symptoms improved. Patients on exemestane plus OFS reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused than did patients on tamoxifen plus OFS; these differences persisted over time. An increase in bone or joint pain was more pronounced, particularly in the short term, in patients on exemestane plus OFS than patients on tamoxifen plus OFS. Changes in global QoL indicators from baseline were small and similar between treatments over the 5 years. INTERPRETATION Overall, from a QoL perspective, there is no strong indication to favour either exemestane plus OFS or tamoxifen plus OFS. The distinct effects of the two treatments on the burden of endocrine symptoms need to be addressed with patients individually. FUNDING Pfizer, International Breast Cancer Study Group, and US National Cancer Institute.

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.

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.

Quantitative Immunohistochemical Analysis Reveals Association between Sodium Iodide Symporter and Estrogen Receptor Expression in Breast Cancer

Background Human sodium iodide symporter (hNIS) gene over-expression is under active consideration worldwide as an alternative target molecule for breast cancer (BC) diagnosis and targeted radio-iodine treatment. However, the field demands better stratified analysis of endogenous hNIS expression across major BC subtypes. Therefore, we have analyzed subtype-specific variation of hNIS overexpression in breast tumor tissue samples by immunohistochemistry (IHC) and also report the development of a homogeneous, quantitative analysis method of digital IHC images. Methods hNIS expression was analyzed from 108 BC tissue samples by IHC. Sub-cellular localization of hNIS protein was analyzed by dual immunofluorescence (IF) staining method using hNIS and HER2 antibodies. An ImageJ based two-step digital analysis method was developed and applied for the bias-free analysis of the images. Results Staining of the tumor samples show 70% cases are hNIS positive indicating high incidence of hNIS positive cases in BC. More importantly, a subtype specific analysis done for the first time shows that hNIS expression is overly dominated in estrogen receptor (ER) positive cases than the receptor negative cases. Further, 56% of the ER+ve, PgR+ve, HER2-ve and 36% of ER+ve, PgR+ve, HER2+ve cases show highest intensity staining equivalent to the thyroid tissue. A significant positive correlation is also observed between hNIS and estrogen receptor expression (p = 0.0033, CI = 95%) suggesting hNIS mediated targeted radio-iodine therapy procedures may benefit both ER+ve, PgR+ve, HER2–ve as well as HER2+ve cases. Further, in a few cases, hNIS and HER2 protein localization is demonstrated by overlapping membrane co-expression. ImageJ based image analysis method shows over 70% match with manual pathological scoring method. Conclusion The study indicates a positive link between hNIS and ER expression in BC. The quantitative IHC image analysis method reported here will further help in patient stratification and potentially benefit global clinical assessment where hNIS mediated targeted 131I radio-ablative therapy is aimed.

Hormone receptors over the last 8 years in a cancer referral center in India: what was and what is?

This study was carried out to observe the trend in hormone receptors over the last 8 years in a tertiary cancer center in India. A total of 11,780 tumors analyzed for hormone receptors over the last 7 years were compared with the results of hormone receptor expression in a prior published study on 798 cases of breast cancer from the same institute. The patients ages ranged from 18 to 102 years, Sixty percent of the patients were in the age group of 31-50 years. Seventy percent of the tumors were grade III tumors. The percentage of hormone receptor expression in breast cancer in the last 8 years varied from 52 to 57%. The overall receptor expression in the last 8 years shifted within a 5% range, confirming that the hormone receptor expression in Indian patients with breast cancer is low. However, there was redistribution within the pattern of estrogen receptor (ER) and progesterone receptor (PR) expression among tumors showing hormone receptor expression. Breast cancers showing only PR expression reduced dramatically from 21% in the year 1999 to in the year 2006, with a parallel increase in breast cancers showing combined ER and PR positivity (from 25 to 41.8%) and only ER expression (from 7.4 to 10.6%). The hormone receptor expression in breast cancers in India is and continues to be low but the high incidence of only PR-positive tumors in our population reported earlier was misrepresented.

Adjuvant Tamoxifen Plus Ovarian Function Suppression Versus Tamoxifen Alone in Premenopausal Women With Early Breast Cancer: Patient-Reported Outcomes in the Suppression of Ovarian Function Trial

PURPOSE The Suppression of Ovarian Function trial showed improved disease control for tamoxifen plus ovarian function suppression (OFS) compared with tamoxifen alone for the cohort of premenopausal patients who received prior chemotherapy. We present the patient-reported outcomes. PATIENTS AND METHODS The quality-of-life (QoL) analysis includes 1,722 of 2,045 premenopausal patients with hormone receptor-positive breast cancer randomly assigned to receive adjuvant treatment with 5 years of tamoxifen plus OFS or tamoxifen alone. Chemotherapy use before enrollment was optional. Patients completed a QoL form consisting of global and symptom indicators at baseline, every 6 months for 24 months, and annually during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6, 24, and 60 months with mixed models for repeated measures with and without chemotherapy and overall. RESULTS Patients on tamoxifen plus OFS were more affected than patients on tamoxifen alone by hot flushes at 6 and 24 months, by loss of sexual interest and sleep disturbance at 6 months, and by vaginal dryness up to 60 months. Without prior chemotherapy, patients on tamoxifen alone reported more vaginal discharge over the 5 years than patients on tamoxifen plus OFS. Symptom-specific treatment differences at 6 months were less pronounced in patients with prior chemotherapy. Changes in global QoL indicators from baseline were small and similar between treatments over the whole treatment period. CONCLUSION Overall, OFS added to tamoxifen resulted in worse endocrine symptoms and sexual functioning during the first 2 years of treatment, with variable magnitudes of treatment differences. Short-term differences in symptom-specific QoL, treatment burden, and coping effort between treatment groups were less pronounced for patients with prior chemotherapy, the cohort that benefited most from OFS in terms of disease control.

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.

Quality of life after accelerated partial breast irradiation in early breast cancer: matched pair analysis with protracted whole breast radiotherapy.

AIMS To compare the quality of life of women with early breast cancer treated with either accelerated partial breast irradiation (APBI) or whole breast radiotherapy (WBRT). MATERIALS AND METHODS After matching for the American Brachytherapy Society criteria, the general European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the breast cancer-specific BR23 modules were given to 48 women (23 APBI and 25 WBRT) who attended the radiotherapy clinic between May 2006 and December 2006 at Tata Memorial Hospital. RESULTS The median follow-up of patients in both groups was 3 years. The reliability and validity of the English and translated versions of the questionnaires were tested by Cronbach alpha (0.67-0.96) and Pearsons correlation for scale-scale correlation statistic (0.013-0.505). The scores for social functioning and financial difficulties in QLQ-C30 showed a trend towards a better outcome in the APBI group (P=0.025 and 0.019, respectively) and body image in BR23 was significantly better in the APBI group as compared with the WBRT group (P=0.005). When the analysis was restricted to women receiving chemotherapy in order to eliminate the confounding effect of the heterogeneous use of chemotherapy in the WBRT group, the difference in social functioning was not significant. However, financial difficulties and body image showed a trend towards a worse outcome in the WBRT group. CONCLUSION Favourable long-term results of APBI in terms of superior body image perception and lesser financial difficulties compared with WBRT need to be confirmed in larger prospective studies investigating the effect of APBI on quality of life and health economics in different ethnic groups and health care set-ups.

INFLUENCE OF SURGICAL TECHNIQUE ON AXILLARY SEROMA FORMATION: A RANDOMIZED STUDY

The aim of this study was to evaluate the influence of surgical technique in the form of electrocautery and suction drains on seroma formation following surgery for breast cancer. A prospective randomized study was carried out. One hundred and sixty patients with breast cancer who underwent surgery were allocated to four arms using a 2 × 2 factorial design. This method enabled us to evaluate the independent effect of two different causative factors on the incidence of postoperative seroma formation using a single dataset with limited numbers. The main outcome measure was postoperative seroma formation defined as a postoperative axillary collection requiring more than one aspiration after removal of the drain. The incidence of seroma in our institution is 90%. Incidence of postoperative seroma was 88.3% if electrocautery was used, which reduced to 82.2% if surgery was carried out using scissors for dissection and ligatures for haemostasis (P = 0.358). There was no influence on the incidence of seroma formation whether suction drain (84.6%) or corrugated drains (86.1%) were used (P = 0.822). The use of electrocautery in axillary dissection does not adversely affect postoperative seroma formation after surgery for breast cancer. The use of different drainage techniques has no bearing on the postoperative seroma formation. The surgical technique has no influence on the rate of seroma formation after surgery for breast cancer.

Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials.

Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.