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

In this community sample of TRICARE beneficiaries, one in five women diagnosed with HER2-positive non-metastatic breast cancer initiated adjuvant trastuzumab >6 months after breast cancer diagnosis. Patients who experienced a delay in therapy initiation of >6 months after diagnosis had a higher risk of relapse, death, or relapse/death than patients who initiated trastuzumab ≤6 months after diagnosis; this higher risk became apparent 1 year after initiation of the trastuzumab treatment.

Since most previous studies did not provide information on the HER2 status of patients and used different definitions of delays in treatment, direct comparison of results is difficult. The only study investigating the impact of therapy delay among trastuzumab-treated patients with HER2-positive breast cancer found a higher risk of death among patients initiating adjuvant therapy >60 days after breast surgery compared with those initiating therapy within 30 days of surgery [35]. These results support the current study’s finding of an increased mortality risk associated with delays in the initiation of adjuvant therapy after breast cancer diagnosis. A few other studies that stratified the analyses by hormone receptor (ER) status, another factor associated with worse prognosis [28, 33], had mixed results. Lohrisch et al. [28] found that delays of >12–24 weeks (vs. ≤12 weeks) in chemotherapy initiation after surgery were associated with significantly worse OS only in ER-positive patients. However, Colleoni et al. [33] found that chemotherapy initiation in node-positive patients within 21–86 days (vs. <21 days) of surgery had a detrimental effect on OS in ER-negative but not in ER-positive patients. Nevertheless, the current study adds to the results of prior studies [33, 35], suggesting that patients with more aggressive breast cancer subtypes may benefit most from early therapy. However, further analyses stratifying patients by prognostic factors at diagnosis would be necessary to confirm this hypothesis.

Previous studies also used different cut-offs to define delays in treatment, such as >21 days [30], 21–86 days [33], 36–89 days [31], >9 weeks [32], 12–24 weeks [28], and >3 months [27, 29] after surgery. In general, studies with short cut-offs did not find an association between delays in adjuvant therapy and OS and/or RFS [30‐32], while treatment delay was associated with a significant increase in the risk of death and/or relapse in studies with longer cut-offs [27‐29]. Nevertheless, even short delays post-surgery (of 21–86 days among ER-negative patients [33] or of >60 days among HER2-positive patients [35]) were associated with an increase in the risk of death/relapse. Overall, these results suggest that the longer the delay in the initiation of adjuvant therapy and the more aggressive the tumor type, the stronger the impact of the delay in treatment on relapse, OS, and RFS outcomes. In the first sensitivity analysis, where delay was defined based on the time to adjuvant therapy initiation rather than time to trastuzumab initiation, the effect was generally stronger, suggesting that a delay in adjuvant therapy initiation of >6 months had a substantial impact on the risk of relapse and death. Conversely, in the sensitivity analysis where cohorts were defined based on a delay of 4 months between diagnosis and adjuvant therapy initiation, the overall impact was weaker, and the impact on the risk of death lost statistical significance.

Importantly, most studies to date defined adjuvant therapy delay using the date of surgery, whereas the current study’s definition uses the breast cancer diagnosis date. Study designs that define therapy delay as starting with the date of surgery ignore the inevitable association between delays in surgery and delays in the initiation of adjuvant therapy among patients who do not receive neoadjuvant therapy (i.e., patients in whom delays in surgery are not justified by the need to downsize a large tumor). If delays in surgery are correlated with delays in adjuvant therapy or reduce the benefits of adjuvant therapy, ignoring the delay in surgery could bias estimates of mortality risks. To address this limitation, two prior studies [27, 28] excluded patients with long intervals between the diagnosis and the surgery (>6 months [27] and >17 weeks [28]). This approach, however, limited the results’ generalizability.

In the current study, the time to adjuvant trastuzumab therapy was defined as a combination of three intervals: the time between (1) diagnosis and surgery, (2) surgery and adjuvant therapy initiation, and (3) adjuvant therapy initiation and the first trastuzumab treatment (applicable to ACTH and other chemotherapy regimens with delayed trastuzumab initiation). The study did not attempt to identify the individual effect of each interval on patients’ outcomes. While this approach has limitations, the result is more generalizable for clinical practice: regardless of the timing of the surgery, initiation of adjuvant therapy >6 months following the breast cancer diagnosis might worsen OS and RFS in patients with HER2-positive tumors. Exploratory analyses among the 552 patients in the “delay” cohort suggested that patterns of delay may be treatment specific: depending on the treatment regimen, the interval accounting for most of the delay was either the time from diagnosis to surgery (i.e., TCH-like regimens, median 4.8 months) or the time from surgery to adjuvant therapy initiation (i.e., trastuzumab monotherapy, median 7.6 months; trastuzumab + taxanes, median 4.7 months) or the time from adjuvant therapy initiation to first trastuzumab (i.e., ACTH-like regimens, median 4.6 months). However, further studies are needed to investigate factors driving these delays. Clinical factors may include post-operation complications, plastic surgery procedures, or adverse effects of therapies initiated prior to trastuzumab; non-clinical factors, which are more amenable to interventions, may include wait times for imaging procedures and appointments with reconstructive plastic surgeons or fertility specialists, personal preferences for seeking second opinions, or financial and geographical constraints.

In this study sample, 11.2 % of the patients received adjuvant trastuzumab monotherapy as their first treatment after breast cancer surgery. A minority of patients who refuse chemotherapy may be directed toward trastuzumab monotherapy, while others may have comorbidities that limit their potential use of chemotherapies. However, it is unlikely that these factors alone explain the use of trastuzumab monotherapy in the study sample. Further studies are needed to understand the selection of trastuzumab monotherapy treatment in certain patients. Another finding was that 51.9 % of the patients in the study sample had mastectomies, that is more than the <50 % benchmark proposed by the America College of Surgeons/National Accreditation Program for Breast Centers [44]. However, >50 % of the patients in the study had stage II or III disease, a slightly higher percentage than the general population initially diagnosed with breast cancer [45]. In addition, these patients did not receive neoadjuvant chemotherapy to reduce the size of the primary tumor, which may have made successful breast conservation surgery more difficult.

This study was subject to the general limitations of claims data, such as occasional coding inaccuracies. These likely affect both study cohorts to a similar extent and may result in a dilution of the observed effect for the delay of trastuzumab treatment. Additionally, since this is a claims-based observational study, some potential confounders may not have been measured and adjusted for in the analyses. Other study limitations include the identification of relapses through a claims-based algorithm that relies on diagnoses of secondary neoplasms, treatment interruption, and treatment re-initiations. While this algorithm was shown to have 90 % sensitivity and 90 % specificity when validated against the recurrence records from the ACTUR [40], some misclassification of relapse events could have occurred. Second, adjuvant therapy regimens were identified from claims based on the chemotherapy and targeted agents used from breast cancer surgery up to 28 days after trastuzumab initiation, and therefore, some misclassification of the adjuvant therapy regimens is possible. Third, patients treated with neoadjuvant therapy were excluded because delays in surgery/initiation of adjuvant trastuzumab therapy may be justified when treating locally advanced disease or large tumors. However, only <15 % of the sample was excluded based on this criterion. Finally, a 6-month cut-off was used to define “delays” in trastuzumab therapy initiation. The optimal time of treatment initiation may vary based on patient characteristics, some of which are unobservable, and a single cut-off at 6 months post diagnosis may result in some misclassification of the patients in the “delay” versus “no delay” cohorts. However, the effect of delay weakened in the sensitivity analyses with a shorter cut-off (4 months), suggesting a longer cut-off is more likely to capture the impact of treatment delays on relapse and/or death outcomes.