PubMed | Dana-Farber Cancer Institute, Italian National Cancer Institute, Ospedale degli Infermi, International Breast Cancer Study Group and 3 more.
Type: Journal Article | Journal: Breast cancer research and treatment | Year: 2016
The purpose of this study was to assess the prognostic and predictive value of tumor-infiltrating lymphocytes (TILs) in the triple-negative breast cancer (TNBC) cohort of the phase III IBCSG trial 22-00, comparing low-dose oral metronomic cyclophosphamide-methotrexate maintenance chemotherapy (CM-maintenance) to no-CM-maintenance in early breast cancer. TILs were evaluated in full-face hematoxylin-and-eosin-stained sections of tumor samples confirmed centrally as TNBC (<1% of ER and PgR immunoreactivity and absence of HER2 overexpression or amplification). Mononuclear cells were evaluated in the stromal area within the borders of the invasive tumor. The primary endpoint was breast cancer-free interval (BCFI). Cox proportional hazards regression model assessed the association of BCFI and secondary endpoints with TILs score. In the 647 tumor samples, the median percentage of TILs was 18% (IQR=8-40%), with 18% having TILs50% (lymphocyte-predominant breast cancer, LPBC). At a median follow-up of 6.9years, TILs were associated with better prognosis. For every 10% increase of TILs, BCFI risk reduction was 13% (HR 0.87, 95% CI 0.79-0.95,P=0.003). DFS, DRFI, and OS risk reductions were 11% (P=0.005), 16% (P=0.003), and 17% (P<0.001), respectively. Multivariable analysis confirmed the independent prognostic value of TILs. No significant TILs-by-treatment interaction was observed (P=0.39) for associations of TILs with BCFI, although patients with LPBC receiving CM-maintenance had a greater breast cancer risk reduction (HR 0.64,95% CI 0.23-1.78) than those with non-LPBC (TILs<50%) (HR 0.96, 95% CI 0.67-1.40). TILs score is a potent prognostic factor in patients with TNBC. Low-dose chemotherapy confers a greater (not statistically significant) clinical benefit in patients with LPBC.
Colleoni M.,Italian National Cancer Institute |
Colleoni M.,International Breast Cancer Study Group |
Munzone E.,Italian National Cancer Institute
Breast | Year: 2015
Endocrine treatments are key component of the adjuvant strategy for pre-menopausal patients with luminal tumors. Treatment options should be based not only upon the risk of relapse and level of endocrine responsiveness, but also on co-morbidities, preferences of the patient and degree of side effects. Tamoxifen should still be considered as an appropriate endocrine therapy in a large group of premenopausal patients (e.g. lower risk patient, presence of co-morbidities, patient preference). However, the results of the SOFT and TEXT trials, evaluating the value of ovarian function suppression (OFS) as well as the role of adjuvant aromatase inhibitor (AI), raised questions about the use of tamoxifen alone in selected higher risk patient. In the SOFT study, premenopausal patients did not benefit from the addition of OFS, but for those women at sufficient risk of recurrence to deserve adjuvant chemotherapy and who maintained pre-menopausal estradiol, the addition of OFS to tamoxifen reduced the risk of recurrence. Moreover, in the TEXT trial, adjuvant treatment with exemestane plus OFS, as compared with tamoxifen plus OFS, significantly improved disease-free survival, breast cancer-free interval and distant disease-free survival, thus representing a new treatment option. Recent available information on endocrine options for younger patients with luminal tumors support the use of tailored endocrine treatments. Issues specific for younger patients related to pregnancies desire, family planning, safety, quality of life and subjective side effects should be a priority in the therapeutic algorithm. © 2015 Elsevier Ltd.
Pruneri G.,Italian National Cancer Institute |
Pruneri G.,University of Milan |
Vingiani A.,Italian National Cancer Institute |
Vingiani A.,University of Milan |
And 10 more authors.
Annals of Oncology | Year: 2016
Background: Although tumor-infiltrating lymphocytes (TILs) have been associated with a favorable prognosis in triplenegative breast cancer (TNBC) patients, this marker is not currently considered robust enough for entering the clinical practice. In the present study, we assessed the clinical validity of the guidelines recently issued by the International TIL Working Group in a large retrospective series of well-annotated TNBC patients. Patients and methods: TILs were evaluated in all the full-face H & E sections from 897 consecutive TNBC (i.e. tumors with >1% of ER and PgR immunoreactivity and absence of HER2 overexpression or amplification) patients diagnosed and treated at the European Institute of Oncology between 1995 and 2010 (median follow-up 8.2 years, range 6 months to 18 years). All mononuclear cells were evaluated in the stromal area within the borders of the invasive tumor, reported as a percentage value and treated as a continuous variable in survival analysis. Results: The median percentage of TILs was 20%, and 21.9% of the cases had =50% (lymphocyte predominant breast cancer, LPBC) TILs. At univariable survival analysis, TILs were a significant predictor of better disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P < 0.0001). Multivariable analysis confirmed that each 10% increase in TILs strongly predicted better survival, independent of patients' age, lymph node status, tumor size, histological grade, peritumoral vascular invasion and Ki-67 labeling index. Patients with LPBC had a 10-year survival rate of 71%, 84% and 96% for DFS, DDFS and OS, respectively. Stratified analysis revealed a positive correlation between TILs and OS across all the subgroups analyzed. Conclusion: Our data support the analytical validity of the recently issued TILs evaluation guidelines in the clinical practice. © The Author 2015.
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
Bernhard J.,University of Bern |
Luo W.,Dana-Farber Cancer Institute |
Ribi K.,International Breast Cancer Study Group Coordinating Center |
Colleoni M.,European Institute of Oncology and International Breast Cancer Study Group |
And 18 more authors.
The Lancet Oncology | Year: 2015
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 Group's 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. © 2015 Elsevier Ltd.
Aebi S.,Luzerner Kantonsspital |
Aebi S.,University of Bern |
Aebi S.,Swiss Group for Clinical Cancer Research SAKK |
Gelber S.,Dana-Farber Cancer Institute |
And 23 more authors.
The Lancet Oncology | Year: 2014
Background: Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients. Methods: The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-. HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152. Findings: From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection. Interpretation: Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative. Funding: US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG). © 2014 Elsevier Ltd.
Castellano I.,University of Turin |
Allia E.,University of Turin |
Accortanzo V.,SantAnna Hospital |
Vandone A.M.,Molinette Hospital |
And 9 more authors.
Breast Cancer Research and Treatment | Year: 2010
The purpose of this article is to evaluate the prognostic value of androgen receptor (AR) expression in patients with estrogen receptor (ER)-positive breast cancer, treated with endocrine therapy, with or without the addition of chemotherapy. A consecutive series of 953 patients with ER-positive breast cancer, treated between 1998 and 2003, was selected. Repeated immunohistochemistry confirmed the expression of ER in the tumor of 938 patients. AR expression was measured by immunohistochemistry. The Kaplan-Meier method, logrank test and multivariate Cox models were used to explore the impact of AR expression on time to relapse (TTR) and disease specific survival (DSS) in all patients and in subgroups treated with chemo-endocrine therapy or endocrine therapy alone. AR immunoreactivity was assessable in 859 tumors and positive in 609 (70.9%). AR expression was a significant marker of good prognosis for TTR (P = 0.001) and DSS (P < 0.001). This effect was particularly evident in the group of patients receiving chemo-endocrine therapy (TTR (P = 0.015) and DSS (P < 0.001)). Cox models confirmed AR as an independent variable for both TTR (P = 0.003, HR 0.444, 95%CI 0.258-0.765) and DSS (P < 0.001, HR 0.135, 95%CI 0.054-0.337). Thus, we focused on ER-positive luminal B breast cancer that may be selected for chemotherapy because of their more aggressive immunophenotype. In this subset AR expression identified a group of patients with better prognosis for TTR (P = 0.017, HR 0.521, 95%CI 0.306-0.888) and DSS (P = 0.001, HR 0.276, 95% CI 0.130-0.588). AR expression is an independent prognostic factor of better outcome in patients with ER-positive breast cancers. © 2010 Springer Science+Business Media, LLC.
Francis P.A.,Peter MacCallum Cancer Center |
Francis P.A.,St Vincents Hospital |
Francis P.A.,International Breast Cancer Study Group
Breast | Year: 2011
Approximately one in forty women diagnosed with early breast cancer is very young (<35 years) and this age group has a worse prognosis. The inferior prognosis in very young women appears to have two aspects. Very young women present more frequently with tumors with adverse histo-pathologic features. However, even when the histo-pathologic features appear favorable (ie. endocrine responsive tumors), analyses suggest that very young women with hormone receptor positive tumors are a sub-group at particular risk for adverse outcomes, compared to older premenopausal women with similar tumors. Chemotherapy induced amenorrhea has been shown to be associated with better outcomes and very young women are less likely to develop amenorrhea. Trials to determine the optimal adjuvant hormonal therapy for very young women are important. After breast conserving surgery, very young women are at increased risk for local recurrence and require particular attention to adequacy of surgical excision, including DCIS. Younger women undergoing breast conservation benefit from a boost dose of radiation. The option of genetic counseling should be provided to women diagnosed at a very young age. When considering adjuvant systemic treatments, fertility and contraception may be important considerations for this age group. Pregnancy after a diagnosis of adequately treated early breast cancer does not appear to be associated with an increased risk for relapse. Very young women are at higher risk for psycho-social distress and non-compliance with adjuvant systemic therapy. Young women should be informed that lifestyle factors after diagnosis may reduce the risk of recurrence. © 2011 Elsevier Ltd.
Lee C.K.,University of Sydney |
Lord S.J.,University of Sydney |
Stockler M.R.,Sydney Cancer Center Royal Prince Alfred and Concord Hospitals |
Coates A.S.,International Breast Cancer Study Group |
And 2 more authors.
European Journal of Cancer | Year: 2010
Purpose: Randomised controlled trials (RCTs) provide optimal evidence to assess the benefits of new treatments. However, clinicians routinely rely on cross-trial comparisons to assess competing treatments when head-to-head randomised comparisons are unavailable. We investigate the validity of cross-trial comparisons using individual patient data (IPD) where patients received the same treatment protocol. We also examine the extent to which statistical adjustment for baseline characteristics can account for inter-trial differences in outcomes. Patients and methods: We used pooled IPD of 378 women with advanced breast cancer assigned to oral cyclophosphamide, intravenous methotrexate and 5-fluorouracil (CMF) in the control arms of three first-line treatment RCTs (ANZ8101, ANZ8614 and ANZ0001) conducted between 1982 and 2001. The Kaplan-Meier method was used to compare progression-free survival (PFS) and overall survival (OS) across trials. Proportional hazard models were constructed to estimate the hazard rates across trials after adjustment for baseline characteristics. Results: The distribution of baseline characteristics varied across trials. There was a statistically significant difference in survival among women treated with CMF in these trials (logrank p = 0.009). The median OS were 17.7, 10.3 and 10.1 months for 0001, 8101 and 8614, respectively. The hazard ratios for survival, adjusted for baseline characteristics differences, were 1.44 (8614) and 1.45 (8101) compared to 0001 (p = 0.03). PFS did not differ across trials (logrank p = 0.38). Conclusions: Caution should be exercised when interpreting results from historical cross-trial comparisons even if the adjustment of baseline prognostic characteristics can be performed. Cross-trial comparisons have some role in hypothesis-generating, identifying and prioritising promising treatments for further investigation; however RCTs are still essential to guide sound clinical practice. © 2009 Elsevier Ltd. All rights reserved.
Lee C.K.,University of Sydney |
Stockler M.R.,University of Sydney |
Stockler M.R.,Royal Prince Alfred and Concord Hospitals |
Coates A.S.,University of Sydney |
And 5 more authors.
British Journal of Cancer | Year: 2010
Background:Baseline health-related quality of life (QL) is associated with survival in advanced breast cancer. We sought to identify patients who were less likely to respond to chemotherapy and at greater risk of toxicity on the basis of their QL.Methods:We used data from three advanced breast cancer trials in which patients (n378) were treated with cyclophosphamide, methotrexate and 5-fluouracil. Patients self-rated their QL using LASA scales for physical well-being (PWB), mood, pain, nausea/vomiting, appetite and overall QL. Multivariable regression models were constructed to compare overall survival (OS), objective tumour response (OTR), adverse events (AEs) and weight loss according to grouped QL scores.Results:Physical well-being, mood, appetite and overall QL were significant univariable predictors of OS. Physical well-being and appetite remained significant after adjustment for baseline biomedical factors. Poor PWB was associated with lower OTR (odds ratio (OR)0.21, 95% confidence interval (CI) 0.09-0.51), higher risk of non-haematological AEs (OR3.26, 95% CI 1.49-7.15) and greater risk of weight loss (OR 2.37, 95% CI 1.12-5.01) compared with good PWB.Conclusion:In women with advanced breast cancer, PWB and appetite are predictors of chemotherapy response and toxicity as well as survival. Quality of life should be a routine clinical assessment to guide patient selection for chemotherapy and for stratification of patients in clinical trials. © 2010 Cancer Research UK All rights reserved.