The optimal time interval between surgery and initiation of adjuvant chemotherapy for early-stage breast cancer is not well established. Although most physicians aim to initiate adjuvant chemotherapy within a few weeks of surgery, clinical factors may cause delay. The influence of delay on relapse and mortality is uncertain, and whether its impact varies by breast cancer subtype is not well defined.1-6
Key Findings
As reviewed in this issue of The ASCO Post, de Melo Gagliato et al analyzed a retrospective cohort of 6,827 patients with early-stage breast cancer who received adjuvant chemotherapy at The University of Texas MD Anderson Cancer Center and assessed the impact of delay on outcomes.7 On univariate analysis in the study population as a whole, there was no association between the time interval from surgery to initiation of adjuvant chemotherapy and overall survival, distant relapse–free survival, or relapse-free survival.
However, planned exploratory subset analyses revealed a differing impact of delay by breast cancer subtype. Longer time to chemotherapy was associated with inferior overall survival in women with triple-negative breast cancer or those with human epidermal growth factor receptor–2 (HER2)-positive breast cancer treated with trastuzumab (Herceptin), although delay did not impact distant relapse–free survival or relapse-free survival in these subgroups.
Multivariate analysis for the study population as a whole demonstrated a 19% increase in the risk of death, but no significant increase in the risk of relapse, associated with initiation of chemotherapy ≥ 61 days after surgery compared to ≤ 30 days after surgery. Subgroups in which multivariate analysis confirmed a substantial negative impact of delay on survival included triple-negative breast cancer, HER2-positive breast cancer treated with trastuzumab, and stage III breast cancer. Delays ≥ 61 days were also associated with inferior survival for hormone receptor–positive breast cancer, although the magnitude of the impact of delay was less in this subgroup. Importantly, initiation of chemotherapy 31 to 60 days after surgery compared to ≤ 30 days after surgery was not associated with inferior survival for any subgroups except triple-negative breast cancer.7
Conflicting Data
The finding that delays in the initiation of adjuvant chemotherapy result in inferior outcomes is supported by a murine model demonstrating a phase of accelerated growth of residual disease after resection of the primary tumor and by mathematical modeling demonstrating increasing chemotherapy resistance with time.8,9 Despite this, results of prior research regarding how timing of adjuvant chemotherapy influences outcomes have been conflicting.1-6 The majority of the data is retrospective in nature, and randomized trials evaluating the impact of delay on outcomes would be difficult to perform.
To the best of our knowledge, the most informative randomized data can be derived from a seminal study evaluating the optimal sequence of adjuvant radiation and chemotherapy. Long-term follow-up of this study revealed no difference in 10-year rates of distant metastases and death, suggesting no risk in delaying chemotherapy by several weeks.10,11 In contrast, two recent meta-analyses revealed increasing risk of death with each 4-week increase in the interval between surgery and adjuvant chemotherapy.12,13
Corresponding Expectations
It is not surprising that the impact of delay in initiation of adjuvant chemotherapy identified by de Melo Gagliato et al differs by tumor subtype and stage, as it reflects the degree of benefit expected from adjuvant chemotherapy in different situations. For example, women with triple-negative breast cancer or HER2-positive breast cancer treated with trastuzumab gain significant improvements in outcome with adjuvant chemotherapy, and the corresponding impact of delaying such treatment identified by de Melo Gagliato and colleagues is notable.
In contrast, the benefit of adjuvant chemotherapy is lower in hormone receptor–positive tumors, and the corresponding impact of delays in adjuvant chemotherapy is lower in this subtype. Indeed, many of the patients with hormone receptor–positive breast cancer who received chemotherapy in the cohort studied by de Melo Gagliato et al may not have been offered chemotherapy if diagnosed today.7,14-17
Recent data in the neoadjuvant setting also support the principle that earlier initiation of systemic therapy for triple-negative and HER2-positive breast cancer is beneficial. For these tumor types, rates of pathologic complete response after neoadjuvant therapy are high and achievement of pathologic complete response is strongly associated with favorable long-term outcomes.18-22
Reasons for Delay
The conclusions reached by de Melo Gagliato and colleagues regarding the impact of delay of adjuvant chemotherapy are particularly relevant given that recent advances in breast cancer care can delay adjuvant chemotherapy. Vandergrift and colleagues recently reported that the time interval between diagnosis and initiation of adjuvant chemotherapy progressively increased between 2003 and 2009. Factors associated with delayed adjuvant chemotherapy included the use of magnetic resonance imaging (MRI), postmastectomy reconstruction, reexcision due to positive margins, and the use of genomic profiling.23 Other factors that can delay adjuvant chemotherapy include fertility preservation and peridiagnostic genetic testing.24,25
Although the time interval between diagnosis and initiation of chemotherapy increased from 2003 to 2009, the mean time between surgery and chemotherapy was only 6.3 weeks, and many of the diagnostic and therapeutic techniques associated with delayed adjuvant chemotherapy have improved breast cancer care overall.23 Based on the findings of de Melo Gagliato et al, it is not clear that delays of this magnitude are detrimental.26
Strengths and Weaknesses
Strengths of the study by de Melo Gagliato et al include its large size and emphasis on differential effects of delay by tumor subtype. However, the study is limited by its retrospective design, multiple comparisons, lack of information about reasons for delay, and incomplete data regarding other treatments that may impact outcomes (such as endocrine therapy, radiation, and the timing of trastuzumab).27-29
Furthermore, the fact that delay influenced survival without impacting relapse suggests potential bias, as patients with poor health may be unable to initiate chemotherapy quickly and also face competing causes of mortality. An additional limitation of this study is that, while the primary findings relate to stage III, HER2-positive, and triple-negative disease, the bulk of the study cohort was composed of patients with stage I to II, hormone receptor–positive breast cancer. Finally, the median follow-up of 59.3 months may not be sufficient to assess the impact of delay on outcomes for hormone receptor–positive patients due to their risk of late recurrence.30
Implications for Clinical Care
Despite these limitations, the study by de Melo Gagliato et al has messages applicable to clinical care. Perhaps the most important is that the impact of delaying adjuvant chemotherapy varies in accordance with the degree of benefit expected from adjuvant chemotherapy. Thus, it is most important to initiate chemotherapy earlier in women with triple-negative, HER2-positive, and stage III breast cancer. Indeed, it is current practice to treat many such patients in the neoadjuvant setting, providing even earlier systemic therapy.
In addition, the data from de Melo Gagliato et al suggest that the greatest increase in risk associated with delaying adjuvant chemotherapy occurs when the time between surgery and initiation of adjuvant chemotherapy exceeds 60 days, a time interval that is achievable in most cases, even with the use of modern day practices such as MRI, peridiagnostic genetic testing, immediate reconstruction, genomic profiling, and fertility preservation interventions.
It is our conclusion that the findings from de Melo Gagliato et al support the current standard of care. We recommend that clinicians continue to aim to initiate adjuvant chemotherapy within a few weeks of surgery whenever possible and that they be judicious in the use of interventions that may delay chemotherapy, particularly in triple-negative and HER2-positive patients. ■
Disclosure: Dr. Smith has been a consultant for Genomic Health. Dr. Stearns reported no potential conflicts of interest.
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