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      Delay in initiation of adjuvant trastuzumab therapy leads to decreased overall survival and relapse-free survival in patients with HER2-positive non-metastatic breast cancer

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          Trastuzumab reduces the risk of relapse in women with HER2-positive non-metastatic breast cancer, but little information exists on the timing of trastuzumab initiation. The study investigated the impact of delaying the initiation of adjuvant trastuzumab therapy for >6 months after the breast cancer diagnosis on time to relapse, overall survival (OS), and relapse-free survival (RFS) among patients with non-metastatic breast cancer. Adult women with non-metastatic breast cancer who initiated trastuzumab adjuvant therapy without receiving any neoadjuvant therapy were selected from the US Department of Defense health claims database from 01/2003 to 12/2012. Two study cohorts were defined based on the time from breast cancer diagnosis to trastuzumab initiation: >6 months and ≤6 months. The impact of delaying trastuzumab initiation on time to relapse, OS, and RFS was estimated using Cox regression models adjusted for potential confounders. Of 2749 women in the study sample, 79.9 % initiated adjuvant trastuzumab within ≤6 months of diagnosis and 20.1 % initiated adjuvant trastuzumab >6 months after diagnosis. After adjusting for confounders, patients who initiated trastuzumab >6 months after the breast cancer diagnosis had a higher risk of relapse, death, or relapse/death than those who initiated trastuzumab within ≤6 months of diagnosis (hazard ratios [95 % CIs]: 1.51 [1.22–1.87], 1.54 [1.12–2.12], and 1.43 [1.16–1.75]; respectively). The results of this population-based study suggest that delays of >6 months in the initiation of trastuzumab among HER2-positive non-metastatic breast cancer patients are associated with a higher risk of relapse and shorter OS and RFS.

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          The online version of this article (doi:10.1007/s10549-016-3790-3) contains supplementary material, which is available to authorized users.

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          Most cited references 26

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          Diagnostic and Statistical Manual of Mental Disorders (DMS-IV)

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            Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California, 1999-2004.

            Breast cancer research examining either molecular profiles or biomarker subtypes has focused on the estrogen receptor negative/progesterone receptor negative/human epidermal growth factor receptor 2 negative (ER-/PR-/HER2-) and ER-/PR-/HER2+ subtypes. Less is known about the epidemiology or clinical outcome of the other subtypes. This study examines the eight combinations of ER/PR/HER2 in patients with invasive breast cancer. The 5-year relative survival and the distribution among demographic, socioeconomic, and tumor characteristics of each of the subtypes are examined. Using the California Cancer Registry, 61,309 women with primary invasive breast cancer were classified according to ER/PR/HER2 status. Five-year relative survival was computed for the eight subtypes. Bivariate analyses were used to assess the distribution of cases across all subtypes. Multivariate logistic regression was used to compute the adjusted odds of having one of the five subtypes with the best and worst survival. Survival varied from 96% (ER+/PR+/HER2-) to 76% (ER-/PR-/HER2+ and ER-/PR-/HER2-). The four subtypes with the poorest survival were all ER negative. Women who were younger than age 50, non-Hispanic black or Hispanic, of the lowest SES groups, and had stage IV tumors that were undifferentiated were overrepresented in ER-/PR-/HER2+ and triple negative (ER-/PR-/HER2-) subtypes. Asian Pacific Islanders had increased odds (OR = 1.41; 95% confidence interval [CI] = 1.26-1.57) of having the ER-/PR-/HER2+ subtype. Stage III tumors (OR = 1.25; 95% CI = 1.08-1.44) and stage IV tumors (OR = 1.58; 95% CI = 1.27-1.98) had higher odds than stage I tumors of being ER-/PR-/HER2+. Stage IV tumors (OR = 0.54; 95% CI = 0.44-0.67) strongly decreased the odds of the ER-/PR-/HER2- subtype. Poorly differentiated and undifferentiated tumors were over 20 times as likely as well-differentiated tumors of being ER-/PR-/HER2- or ER-/PR-/HER2+. There are considerable differences in survival, demographics, and tumor characteristics among the eight subtypes. We recommend reporting breast cancer as an ER/PR/HER2 subtype and precisely documenting demographic and tumor characteristics.
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              Stage at diagnosis is a key explanation of differences in breast cancer survival across Europe.

              We used multiple regression models to assess the influence of disease stage at diagnosis on the 5-year relative survival of 4,478 patients diagnosed with breast cancer in 1990-1992. The cases were representative samples from 17 population-based cancer registries in 6 European countries (Estonia, France, Italy, Netherlands, Spain and UK) that were combined into 9 regional groups based on similar survival. Five-year relative survival was 79% overall, varying from 98% for early, node-negative (T1N0M0) tumours; 87% for large, node-negative (T2-3N0M0) tumours; 76% for node-positive (T1-3N+M0) tumours and 55% for locally advanced (T4NxM0) tumours to 18% for metastatic (M1) tumours and 69% for tumours of unspecified stage. There was considerable variation across Europe in relative survival within each disease stage, but this was least marked for early node-negative tumours. Overall 5-year relative survival was highest in the French group of Bas-Rhin, Côte d'Or, Hérault and Isère (86%), and lowest in Estonia (66%). These geographic groups were characterised by the highest and lowest percentages of women with early stage disease (T1N0M0: 39% and 9%, respectively). The French, Dutch and Italian groups had the highest percentage of operated cases. The number of axillary nodes examined, a factor influencing nodal status, was highest in Italy and Spain. After adjusting for TNM stage and the number of nodes examined, survival differences were greatly reduced, indicating that for these women, diagnosed with breast cancer in Europe during 1990-1992, the survival differences were mainly due to differences in stage at diagnosis. However, in 3 regional groups, the relative risks of death remained high even after these adjustments, suggesting less than optimal treatment. Screening for breast cancer did not seem to affect the survival patterns once stage had been taken into account. Copyright 2003 Wiley-Liss, Inc.

                Author and article information

                202-877-0928 ,
                Breast Cancer Res Treat
                Breast Cancer Res. Treat
                Breast Cancer Research and Treatment
                Springer US (New York )
                23 April 2016
                23 April 2016
                : 157
                : 145-156
                [ ]Washington Cancer Institute, MedStar Washington Hospital Center, 110 Irving Street, NW, Room C-2149, Washington, DC 20010-2975 USA
                [ ]Virginia Oncology Associates, Virginia Beach, VA USA
                [ ]Genentech, Inc., South San Francisco, CA USA
                [ ]Analysis Group, Inc., Montreal, QC Canada
                [ ]Health ResearchTx LLC, Trevose, VA USA
                [ ]Navy and Marine Corps Public Health Center, Portsmouth, VA USA
                [ ]Analysis Group, Inc., Boston, MA USA
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (, which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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