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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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          Abstract

          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 references26

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          Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000-2007: a population-based study

          Background: We investigate whether differences in breast cancer survival in six high-income countries can be explained by differences in stage at diagnosis using routine data from population-based cancer registries. Methods: We analysed the data on 257 362 women diagnosed with breast cancer during 2000–7 and registered in 13 population-based cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Flexible parametric hazard models were used to estimate net survival and the excess hazard of dying from breast cancer up to 3 years after diagnosis. Results: Age-standardised 3-year net survival was 87–89% in the UK and Denmark, and 91–94% in the other four countries. Stage at diagnosis was relatively advanced in Denmark: only 30% of women had Tumour, Nodes, Metastasis (TNM) stage I disease, compared with 42–45% elsewhere. Women in the UK had low survival for TNM stage III–IV disease compared with other countries. Conclusion: International differences in breast cancer survival are partly explained by differences in stage at diagnosis, and partly by differences in stage-specific survival. Low overall survival arises if the stage distribution is adverse (e.g. Denmark) but stage-specific survival is normal; or if the stage distribution is typical but stage-specific survival is low (e.g. UK). International differences in staging diagnostics and stage-specific cancer therapies should be investigated.
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            Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer.

            For patients with breast cancer (BC), the optimal time to initiation of adjuvant chemotherapy (TTC) after definitive surgery is unknown. We evaluated the association between TTC and survival according to breast cancer subtype and stage at diagnosis. Women diagnosed with BC stages I to III between 1997 and 2011 who received adjuvant chemotherapy at our institution were included. Patients were categorized into three groups according to TTC: ≤ 30, 31 to 60, and ≥ 61 days. Survival outcomes were estimated and compared according to TTC and by BC subtype. Among the 6,827 patients included, the 5-year overall survival (OS), relapse-free survival (RFS), and distant RFS (DRFS) estimates were similar for the different TTC categories. Initiation of chemotherapy ≥ 61 days after surgery was associated with adverse outcomes among patients with stage II (DRFS: hazard ratio [HR], 1.20; 95% CI, 1.02 to 1.43) and stage III (OS: HR, 1.76; 95% CI, 1.26 to 2.46; RFS: HR, 1.34; 95% CI, 1.01 to 1.76; and DRFS: HR, 1.36; 95% CI, 1.02 to 1.80) BC. Patients with triple-negative BC (TNBC) tumors and those with human epidermal growth factor receptor 2 (HER2) -positive tumors treated with trastuzumab who started chemotherapy ≥ 61 days after surgery had worse survival (HR, 1.54; 95% CI, 1.09 to 2.18 and HR, 3.09; 95% CI, 1.49 to 6.39, respectively) compared with those who initiated treatment in the first 30 days after surgery. TTC influenced survival outcomes in the overall study cohort. This finding was particularly meaningful for patients with stage III BC, TNBC, and trastuzumab-treated HER2-positive tumors who experienced worse outcomes when chemotherapy was delayed. Our findings suggest that early initiation of chemotherapy should be granted for patients in these high-risk groups.
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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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                Author and article information

                Contributors
                202-877-0928 , Christopher.Gallagher@medstar.net
                Journal
                Breast Cancer Res Treat
                Breast Cancer Res. Treat
                Breast Cancer Research and Treatment
                Springer US (New York )
                0167-6806
                1573-7217
                23 April 2016
                23 April 2016
                2016
                : 157
                : 145-156
                Affiliations
                [ ]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
                Article
                3790
                10.1007/s10549-016-3790-3
                4869764
                27107569
                aa1182c5-9dc8-4adb-94d4-6a645619938f
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), 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.

                History
                : 16 February 2016
                : 5 April 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004328, Genentech;
                Categories
                Epidemiology
                Custom metadata
                © Springer Science+Business Media New York 2016

                Oncology & Radiotherapy
                her2-positive non-metastatic breast cancer,trastuzumab,overall survival,relapse-free survival

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