Timing of adjuvant chemotherapy initiation following surgery influences survival outcomes in breast cancer

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1. Delays in initiation of adjuvant chemotherapy following definitive breast cancer surgery are associated with worse outcomes in advanced stage disease and worse survival in hormone receptor positive and HER2 positive cancers.

Evidence rating level: 2 (Good)

Study Rundown: Previous clinical trials regarding the use of adjuvant chemotherapy following definitive surgery for breast cancer has shown significant survival benefits. However, the effect of a delay in initiation of therapy on adverse outcomes is less understood. Though animal models and some retrospective studies have suggested a benefit with shorter time to initiation (TTC), it remains unclear if delays have detrimental effects or if there is a differential impact of TTC on different cancer subtypes. Therefore, the purpose of this large, retrospective study was to examine the association between TTC and outcomes among different tumor characteristics and breast cancer subtypes.

The authors concluded that TTC after definitive surgery was significantly associated with survival outcomes for specific patient subgroups based on stage at diagnosis and cancer subtype. Patients with more advanced stage breast cancer at diagnosis experienced worse outcomes with delayed initiation of adjuvant chemotherapy, possibly reflecting the presence of pre-existing micrometastatic disease. Furthermore, delays in starting chemotherapy were associated with a detrimental impact on survival among patients with hormone receptor positive tumors and also with HER2 positive tumors treated with trastuzumab. Based on these results, the authors suggest that early initiation of chemotherapy should be favored.

This study benefited from the large patient population, which allowed for analysis of multiple tumor subtypes. However, it should be noted that this was a retrospective study and that most of the patients involved were stage I or II and were treated at a single center. Longer follow-up times may be required to fully realize the effects of delayed TTC on clinical outcomes.

Click to read the article in JCO

Relevant reading: Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer

In-Depth [retrospective cohort study]: This study was a retrospective review, taking patients from the Breast Medical Oncology Institutional database from the MD Anderson Cancer Center. Included were women with stage I to III invasive primary breast cancer diagnosed between 1997 and 2011 who were treated with definitive surgery followed by adjuvant chemotherapy. Data on estrogen receptor (ER), progesterone receptor (PR), and HER2 status was also obtained, and breast cancer subtypes defined as hormone receptor positive (ER and/or PR positive and HER2 negative), HER2 positive (regardless of hormone receptor status) and triple-negative breast cancer (negative for all receptors) or TNBC. A total of 6827 women were included, with a median follow-up of 59.3 months. They were split into three groups, those with TTC of less than 30 days, 31 to 60 days, or greater than 60 days following surgery. There was no statistically significant relationship between TTC and type of surgery (p = 0.83) or number of comorbidities (p = 0.6). The authors then performed survival analysis, with the major outcomes being relapse-free survival (RFS) measured from chemotherapy initiation, distant relapse-free survival (DRFS) and overall survival (OS). They also split HER2 positive patients by trastuzumab adjuvant use.

The authors found that the 5-year OS, RFS and DRFS were similar across the TTC categorized patient groups, with no statistically significant differences noted. However, differences were noted upon splitting patients by breast cancer subtype and staging. TTC greater than 60 days was associated with worse DRFS (HR 1.2; 95% CI 1.02-1.43) in stage II cancer and worse OS (HR 1.76; 95% CI 1.26-2.46) and DRFS (HR 1.36, 95%CI 1.02-1.8) in stage III cancer. Patients with TNBC tumors and with HER2 tumors treated with trastuzumab in this category also had worse survival (HR 1.54; 95% CI 1.09-2.18 and HR 3.09; 95%CI 1.49-6.39, respectively) compared to those with TTC less than 30 days.

By Monica Parks and Andrew Bishara

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