Comparison of Use of Neoadjuvant Systemic Treatment for Breast Cancer and Short-term Outcomes Before vs During the COVID-19 Era in Ontario, Canada

Key Points Question Did the use of neoadjuvant-intent systemic therapy for patients with breast cancer change after the emergence of COVID-19 in Ontario, Canada? Findings In this cohort study including 10 920 patients, the use of neoadjuvant-intent chemotherapy and hormonal treatment increased during the COVID-19 era, but there was substantial regional variability. Bridging hormonal therapy was a more common adaptation to cancer treatment in the COVID-19 era than neoadjuvant chemotherapy; neoadjuvant-intent systemic treatment was not associated with short-term outcomes in the COVID-19 era. Meaning These findings suggest that patients with breast cancer were more likely to receive neoadjuvant-intent systemic treatment in the COVID-19 era to offset delays in surgical capacity.


Introduction
The COVID-19 pandemic changed the landscape of health care delivery. When infection rates began to rise in Ontario, concerns grew that patients with COVID-19 requiring respiratory support would reduce the capacity of intensive care units for non-COVID-19-related care, as had happened in other jurisdictions that experienced the first wave earlier than Canada (eg, Italy, New York). 1 For patients with cancer, the effects that COVID-19 infection would have on their health status were largely unknown at the time. Given the immunocompromised state of many patients with cancer, the concern was that a COVID-19 infection might portend an even higher chance of morbidity and mortality in this patient population. 2,3 These concerns led to a series of policy changes to alter the care of patients in Ontario and preempt the anticipated surge of patients requiring inpatient acute and critical care beds. To this effect, many nonurgent surgical procedures to treat cancer were postponed. [4][5][6] Consequently, some patients with cancer who were eligible for primary surgical resection could be offered neoadjuvant systemic treatment (ST), with the intent that surgery would occur at a later date when hospital burden had subsided.
By the start of the first wave of the COVID-19 pandemic in Ontario, several ST regimens that previously were only publicly funded in the adjuvant setting were temporarily extended to the neoadjuvant setting. [7][8][9] In the present study, we measured the use of publicly funded neoadjuvantintent ST for patients with breast cancer, examined regional variability, and assessed whether any changes in treatment modality were associated with short-term patient outcomes.

Methods
This was a retrospective, population-based cohort study conducted in Ontario, Canada. Analyses were conducted between June 2020 and November 2021, with all data extracted in November 2021.
Research ethics approval was not required as per an Ontario Health (Cancer Care Ontario) privacy assessment. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

Cohort Identification and Data Sources
Patients were adults (aged at least 18 years) who received ST between March 11, 2019, and September 30, 2020, for a new primary breast cancer. The ST regimens included were determined a priori based on existing or new ST protocols that may be provided in either the neoadjuvant or adjuvant settings and categorized as chemotherapy or hormonal therapy (eTable 1 in the Supplement).
In Ontario, most injectable cancer therapies (eg, intravenous chemotherapy) are funded by the Systemic Treatment-Quality Based Procedures (ST-QBP), identified from the Activity Level Reporting (ALR) database. ALR includes information on ST administered in ambulatory cancer clinics within hospitals across Ontario (99% of all ST administered in the province). Treatment regimen data reported via ALR are for purposes of hospital funding, regardless of funding source for individual drugs included in the regimen. Many oral or take-home cancer drugs (eg, hormones), although sometimes funded by the Ontario Drug Benefit program, are captured by the ALR system when prescriptions are entered using the in-hospital Computerized Provider Order Entry system. 10 Treatment intent is indicated by the most responsible physician (typically a medical oncologist or hematologist) using the Computerized Provider Order Entry system. only ST for the primary disease was captured, patients diagnosed more than 6 months before starting ST were omitted (eFigure 1 in the Supplement).

Regional Variability
We explored whether there was regional variability in the primary outcome.

Statistical Analysis
To evaluate whether patients in the COVID-19 era were more likely than patients in the pre-COVID-19 era to receive neoadjuvant-intent ST vs adjuvant ST, we used logistic regression, presenting odds ratios (ORs) with 95% CIs. We also explored whether sociodemographic characteristics were associated with neoadjuvant-intent ST, and using interaction terms, whether these associations All analyses were conducted at Ontario Health using SAS version 9.4 (SAS Institute) and cumulative incidence plots using R version 1.2.5033 (R Project for Statistical Computing). Results were considered statistically significant at a 2-tailed P < .05.

Patient Outcomes: Receipt of Surgery
Among patients receiving neoadjuvant-intent breast chemotherapy, receipt of surgery followed a similar pattern between the pre-COVID-19 and COVID-19 eras, increasing sharply at the time chemotherapy is expected to have been completed (14-18 weeks after starting chemotherapy) and leveling off after 6 months ( Figure 3A). By the end of follow-up, 81% and 75% of patients subsequently received surgery in the pre-COVID-19 and COVID-19 eras, respectively (log-rank  era were significantly more likely to receive subsequent surgery than in the pre-COVID-19 era (HR, 3.17; 95% CI, 2.75-3.65; log-rank P < .001) ( Figure 3B).

Discussion
In this study, we observed greater use of neoadjuvant-intent ST in the COVID-19 era compared with the pre-COVID-19 era for breast cancer patients receiving ST within 6 months of diagnosis. There was significant regional variation in the use of neoadjuvant-intent ST that was not associated with regional COVID-19 infection rates.
In response to COVID-19, the use of neoadjuvant ST increased in the United States, 13 Brazil, 14 Turkey, 15 and elsewhere. 16 In Australia, where there was a low burden of COVID-19 at the time, any changes in the dispensation of chemotherapy was small and transitory, driven by immunotherapies and targeted therapies. 17 In contrast, the number of registrations for neoadjuvant-intent ST decreased in England and Italy due to 19 In the United Kingdom, following multidisciplinary consultation many patients with breast cancer had incomplete neoadjuvant chemotherapy or instead received adjuvant chemotherapy. 20 More frequent use of neoadjuvant endocrine therapy for breast cancer patients was reported from the United Kingdom and the United States with substantial regional variability (similar to our findings). 20,21 Although not all cancers are suitable for neoadjuvant ST, substantial attention has been placed on breast cancer because of the array of biomolecular subtypes that can be used to identify patients who may have at least a neutral response to delaying surgery. 22,23 For example, patients with hormone receptor-positive/ERBB2negative stage I-III breast cancer can be treated with neoadjuvant endocrine therapy for 6 to 12 months before receiving surgery. 13,24 Although we do not have timely data on stage and molecular subtype, our results suggest that the population of patients with breast cancer receiving neoadjuvant-intent hormonal agents in the pre-COVID-19 era differed from that of the COVID-19 era.
These hormone-first patients were more likely to receive surgery in the COVID-19 era than the pre-COVID-19 era, suggesting that this group contains a subpopulation of patients whose treatment was truly being temporized due to COVID-19. In the pre-COVID-19 era, neoadjuvant hormones were not typically used unless the tumor was deemed unresectable. 25 In the COVID-19 era, however, operating room availability was limited, so patients who otherwise would have received adjuvant hormones instead received bridging hormonal therapy for a few months before surgery. ED visits and

Limitations
One limitation is misclassifying patients as receiving curative-intent treatment, particularly among the ST-only subgroup. However, we expect such misclassification to be non-differential between the periods. Moreover, we assume that all surgical procedures were performed with curative intent, but it is also possible that the type of surgery performed in the COVID-19 era differed from the pre-COVID-19 era. Another source of misclassification is the time point chosen to separate the pre-COVID-19 era from the COVID-19 era. Treatments starting shortly after this date likely follow treatment plans that originated in the pre-COVID-19 era. We expect this to shift the association of the COVID-19 era on the odds of providing neoadjuvant-intent ST toward unity. Another limitation is the potential for missing data on oral ST, particularly hormonal therapy. Although ALR captures many of these treatments, some may be missed. Another limitation is unavailability of timely staging and biomarker data. These data would be important to explore the potential misclassification of palliative-intent patients, and also to contextualize the findings in the face of possible stage migration. 28 Lastly, patients who did not start therapy (surgery or ST) within 6 months of diagnosis due to avoidance of health care were not included. This represents a distinct population of patients whose outcomes and treatment may differ from those included in this study.

Conclusions
We observed a higher proportion of patients receiving neoadjuvant-intent ST within 6 months of cancer diagnosis in Ontario during the COVID-19 era. Although there were no substantial detrimental short-term outcomes, whether these deviations in standard-of-care treatment influence long-term patient outcomes remains to be seen.