Impact of delays in neoadjuvant chemotherapy initiation on pathologic complete response among patients with HER2-positive or triple negative breast cancer.
Authors: Wooster Margaux , DeStephano David , Beauchemin Melissa P. , Wang Shikun , Hur Chin , Wright Jason Dennis , Hershman Dawn L. , Accordino Melissa Kate 
Published: September 2024

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Background:
Pathologic complete response (pCR) is used as a surrogate endpoint for overall survival (OS) in high-risk early-stage breast cancer (BC). pCR rates vary according to BC molecular subtype and have the highest association with OS in triple negative BC (TNBC) and HER2-positive (HER2+) BC. In these subgroups, neoadjuvant chemotherapy (NACT) is often the standard of care. We evaluated the association of delays in NACT initiation (NACTI) with pCR.
Methods:
We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis cT2+ or lymph node positive HER2+ or TNBC between 1/1/2010 – 12/31/2020, who were treated with NACT within 180 days of BC diagnosis. Time to chemotherapy (TTC) was recorded in days. Patients were categorized by receptor status. We used AJCC 7
th
and 8
th
edition T and N staging to define pCR (pT0 or pTis and pN0 or pN0I-). Delay was defined as TTC > 60 days. Multivariable logistic regression, adjusted for demographic, socioeconomic and tumor characteristics, was used to calculate odds of pCR associated with delays. A sensitivity analysis defining delay >30 and >90 days was also conducted.
Results:
We identified 105,352 eligible patients, 73% were White, 19% were Black, 3% were Asian, and 4% were Other/Unknown. Median age at diagnosis was 52 years (range 18-90), median TTC was 32 days (range 0-180). There were 56,868 patients with HER2+ BC and 48,484 with TNBC; 9% of patients were delayed > 60 days in each group. Among all HER2+ patients, 39.1% achieved a pCR: 35.0% with delay compared to 39.5% without delay. Among TNBC patients, 30% achieved a pCR: 25% with delay compared to 31% without delay (p < 0.0001 for all). In multivariable analysis, patients with HER2+ disease (OR 0.85, 95%CI 0.79-0.92) and TNBC (OR 0.80, 95%CI 0.73-0.87) were less likely to achieve pCR if delayed > 60 days. In a sensitivity analysis, delay > 30 days was associated with lower likelihood of achieving pCR for all and delay > 90 days was associated with lower likelihood for TNBC (Table).
Conclusions:
Delays in NACTI >60 days among patients with HER2+ and TNBC BC was an independent predictor of not achieving pCR. Given the known association between socioeconomic factors and delays to initiation of treatment, interventions aimed at reducing delays may reduce disparities in BC outcomes. Future studies to identify causes of delays and the downstream impact are needed to ultimately develop interventions that mitigate these effects among patients with HER2+ or TNBC, where pCR rates are associated with OS.

Association of pCR in patients who experience NACTI delay using multivariable logistic regression* n(complete case) = 77,690.

Subgroup
>30-day Delay in NACTIOR (95% CI)
>60-day Delay in NACTIOR (95% CI)
>90-day Delay in NACTIOR (95% CI)

HER2+n =41,672

0.91 (0.87-0.95)

0.85 (0.79-0.92)

0.93 (0.80-1.07)

TNBCn = 36,018

0.87 (0.83-0.92)

0.80 (0.73-0.87)

0.78 (0.65-0.92)

*Adjusted for demographic, socioeconomic and tumor characteristics.