key: cord-0784797-eybkivte
authors: Minami, Christina A.; Kantor, Olga; Weiss, Anna; Nakhlis, Faina; King, Tari A.; Mittendorf, Elizabeth A.
title: Association between Time to Operation and Pathological Stage in Ductal Carcinoma in Situ and Early-Stage Hormone Receptor-Positive Breast Cancer
date: 2020-08-06
journal: J Am Coll Surg
DOI: 10.1016/j.jamcollsurg.2020.06.021
sha: b4c410c8b776f2bee7b094c4302139f8b12ed7e5
doc_id: 784797
cord_uid: eybkivte

BACKGROUND: During the COVID-19 pandemic, surgical delays have been common for patients with ductal carcinoma in situ (DCIS) and early-stage estrogen receptor-positive (ER+) breast cancer, often in favor of neoadjuvant endocrine therapy (NET). To understand possible ramifications of these delays, we examined the association between time to surgery (TTS), pathological staging and overall survival (OS). STUDY DESIGN: Patients with DCIS or ER+ cT1-2N0 breast cancer treated 2010-2016 were identified in the National Cancer Database. TTS was recorded. Factors associated with pathological upstaging were examined using logistic regression analyses. Cox proportional hazard models were used to analyze OS. Analyses were stratified by disease stage and initial treatment strategy. RESULTS: 378,839 patients were identified. Among those undergoing primary surgery, TTS was within 120 days in >98% in all groups. Among cT1-2N0 patients selected for NET, surgery was performed within 120 days in 59.6% of cT1N0 and 30.9% of cT2N0 patients. Increased TTS was associated with increased odds of pathological upstaging in DCIS patients (ER+: 60-120 days: OR:1.15, 95% CI:1.08-1.22; >120 days: OR:1.44, 95% CI:1.24-1.68; ER-: 60-120 days: NS; >120 days: OR:1.36, 95% CI:1.01-1.82; <60 days: reference), but not in patients with invasive cancer irrespective of initial treatment strategy. No difference in OS was seen by TTS in DCIS or NET patients. CONCLUSION: Increased TTS was associated with a small increase in pathological upstaging in DCIS patients, but did not impact OS. In patients with cT1-2N0 disease, NET use did not impact stage or OS, supporting the safety of delay strategies in ER+ breast cancer patients during the pandemic.

To minimize patient exposure and preserve hospital resources during the COVID-19 pandemic, hospitals across the U.S were asked to sharply decrease the volume of non-urgent surgical cases, including oncologic procedures. The COVID-19 Pandemic Breast Cancer Consortium released recommendations regarding prioritization of breast cancer operations to aid decision-making, with the recognition that little prospective data existed regarding the repercussions of the suggested strategies. 1 It was recommended that operations for ductal carcinoma in situ (DCIS) be deferred until after resolution of the pandemic, with suggested initiation of neoadjuvant endocrine therapy (NET) in patients with estrogen receptor-positive (ER+) DCIS. NET was similarly recommended as the preferred strategy for patients with earlystage ER+ invasive breast cancer.

The impact of time to surgery (TTS) on breast cancer outcomes in these very early stage patients remains unclear. Time to surgery has been shown to be associated with increase in upstaging from DCIS to invasive disease, on the order of 1% per month, but with excellent survival rates even in upstaged patients. 2 In invasive cancer patients, studies using nodal positivity as a surrogate outcome measure have demonstrated mixed results. 3, 4 Moreover, survival analyses have similarly reported varied findings, thus leaving surgeons without a clear sense of the repercussions that may result from treatment delays.

NET use has primarily been utilized in patients with stage II and III ER+ disease, demonstrating tumor responses comparable to those seen with neoadjuvant chemotherapy. 5, 6 Survival data in NET patients are more difficult to interpret, not only because of the long disease-free intervals associated with ER+ disease, but also because adjuvant treatment pathways are not standardized in NET patients. 5, 7 There are definitive data in older adults with ER+ disease that demonstrate no overall survival (OS) difference between primary endocrine therapy alone versus surgery plus endocrine therapy. [8] [9] [10] Use of NET as a delay strategy during the pandemic in patients with early-stage ER+ disease thus has a basis in high-quality evidence, but given the historical selection bias for NET in post-menopausal patients, it does to a certain extent, represent an extrapolation of existing data to a broader population.

The true oncologic ramifications of these delay strategies will be observed over time.

Understanding the possible outcomes earlier, however, could be useful in effectively counseling and reassuring patients regarding surgical delays and the broadened use of NET. Our primary objective was to understand the possible effects of COVID-related surgical delays on breast oncology outcomes by examining the association between TTS and pathological staging, with secondary analyses evaluating OS and extent of breast surgery. Cancer Consortium, the population of interest was patients with DCIS or early-stage (cT1-2N0) ER+ disease. 1 Patients who were treated outside the reporting facility, had unknown ER status, unknown surgical timing, unknown surgical pathology data, or who underwent more than one surgery were excluded. In addition, patients who did not undergo surgery within a year of diagnosis, who received neoadjuvant chemotherapy, or in the case of patients with invasive disease, those who did not receive endocrine therapy at all were excluded. An exceedingly small number of patients with DCIS received NET, precluding reliable analysis of this subpopulation, and were thus excluded. The remaining 99,749 DCIS patients, 222,933 cT1N0, and 56,157 cT2N0 patients were assessed (Figure 1 ).

The exposure of interest was TTS from time of diagnosis, originally defined as <30, 31-60, 61-90, 91-120, and >120 days. As outcomes of interest did not significantly vary from 0-30 vs 30-60 days nor from 60-90 vs 90-120 days, these categories were collapsed into <60 days, 61-120 days, and >120 days. Patient-level variables included age (18-39, 40-49, 50-59, 60-69, and 70-79, and >80 years old), race/ethnicity (white, black, Hispanic, Asian, and other/unknown), insurance status (private, Medicare, Medicaid, uninsured, and other/unknown), regional location of the patient's home zip code (metropolitan, urban, or rural). Disease characteristics included tumor grade (classified as 1, 2, 3) and tumor histology (ductal, lobular, mixed). Both clinical and pathological tumor category (Tis, T1, T2, T3, T4) and nodal category (Nx, N0, N1, N2, N3) were included. Treatment characteristics included surgery type (breast-conserving surgery [BCS] versus mastectomy), radiation therapy (yes/no), and adjuvant chemotherapy (yes/no). Facility type was also incorporated, defined by CoC accreditation status as a community cancer program, comprehensive community cancer program, academic/research program, or integrated network cancer program.

The main measure of interest was the proportion of DCIS, cT1N0, and cT2N0 patients who were upstaged on final surgical pathology. Inclusion criteria were based on T and N categories, while the outcome measure was based on the 8 th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. 11 Patients included in the cT1N0 and cT2N0 groups were re-coded by the 8 th edition clinical prognostic staging criteria and were deemed "upstaged" if their pathological prognostic stage was higher than their clinical prognostic stage. Secondary outcome measures were 5-year OS and type of breast surgery (BCS versus mastectomy).

Time to surgery was treated as a categorical variable, defined by the date of diagnosis to the date of surgery. All tests were two-sided with a p-value <0.05 considered statistically significant. Analyses were stratified by clinical staging upon presentation (DCIS, cT1N0, cT2N0); all DCIS patients (ER+ and ER-) underwent upfront surgery, while the cT1N0 and cT2N0 groups were further stratified by initial treatment strategy (NET vs primary surgery). Chisquare tests of proportion were performed to test the significance of baseline differences in the study population. Univariable logistic regression models were used to examine factors associated with pathological upstaging (eTable 1). To test the significance of TTS controlled for all other patient and hospital covariates, a multivariable analysis was performed using a random intercept, fixed slope, logistic regression model with the hospital as a random effect. Variables for this model were chosen a priori, and included age, race, Charlson comorbidity index (CCI) score, insurance status, facility type, tumor histology, surgery type, and TTS. Tumor grade was not included in this model given that it is a significant part of the 8 th edition prognostic pathological staging system (i.e. the outcome variable). A multivariable logistic regression model was also performed to determine significant factors associated with receipt of NET. Cox proportional hazards models-adjusted for age, race, comorbidity index, tumor grade, histology, surgery type, pathologic tumor and nodal category, and adjuvant therapy (chemotherapy and radiation therapy)-were used to compare OS by time from diagnosis to surgery by clinical disease stage (DCIS, cT1N0, cT2N0), and initial treatment strategy (NET versus primary surgery). All analyses were performed using SPSS 19.0 (SPSS Corp., Armonk, NY). 

In total, a greater proportion of patients with ER-DCIS (17.6%) were upstaged to invasive disease as compared to patients with ER+ DCIS (10.4%) ( Table 2 ). The proportion of patients who were upstaged on final pathology increased by TTS among both the ER+ and ER-DCIS patients (Figure 2 , p<0.001 for both). A small group of patients (<5%) had invasive disease on final pathology but were missing elements (e.g. grade or nodal status) needed to accurately stage them per the 8 th edition prognostic pathological staging criteria, and were thus coded as being upstaged, yet "unknown." Among the statistically significant factors associated with pathological upstaging among ER+ DCIS patients on adjusted analysis was TTS, as patients undergoing surgery >60 days after diagnosis had an OR of 1.15 (95% CI 1.08-1.22) compared to those who underwent surgery within the first 60 days (Table 3) . Patients with ER-DCIS also had higher odds of being upstaged, but only if they underwent surgery >120 days after diagnosis (OR In total, a larger proportion of T1N0 NET patients (9.7%) were upstaged as compared to the T2N0 NET patients (4.8%) ( Table 2 ). The proportion of patients who were upstaged on final pathology increased by time to surgery among the T1N0 NET patients (p<0.03) but not the T2N0 NET patients (p=0.455) ( Figure 2 ). Of the cT2N0 NET patients, 80% of those with clinical stage IB disease, 62% of those with stage IIA disease, and 65.5% of those with stage IIB disease were downstaged upon final pathology. On adjusted analysis, NET patients undergoing surgery >60 days after diagnosis were not more likely to be upstaged on final pathology compared to those undergoing surgery in <60 days (Table 3) . Patients with lobular disease were more likely to be upstaged (OR 1.75, 95% CI 1.21-2.53) compared to those with ductal or mixed histologies. NET patients undergoing mastectomy also had higher odds of upstaging on final pathology (OR 3.07, 95% CI 2.26-4.17), although those who were initially staged as having cT2 disease compared to those with cT1 disease were less likely to be upstaged (OR 0.36, 95% CI 0.26-1.47).

Among primary surgery patients, 7.5% of cT1N0 patients and 5.4% of cT2N0 patients were upstaged on final pathology. The proportion of patients who were upstaged increased by TTS (cT1N0: 7.7% in the <60 day group as compared to 11.1% in the >120 day group; cT2N0: 5.4% in the <60 day group as compared to 6.6% in the >120 day group) (p<0.001 for both).

However, on adjusted analysis, TTS was not significantly associated with pathological upstaging. Patients with lobular disease and mixed histologies were more likely to be upstaged (lobular: OR 1.50, 95% CI 1.21-2.53; mixed: 1.13, 95% CI 1.08-1.19) compared to those with a ductal histology. Mastectomy patients in this group, as in the DCIS and NET groups, had higher odds of upstaging on final pathology (OR 2.82, 95% CI 2.73-2.91). As in the NET group, those who were initially staged as having cT2 disease compared to those with cT1 disease were less likely to be upstaged (OR 0.47, 95% CI 0.45-0.49).

The median follow-up time ranged from 33.7 months to 42.4 months by subgroup (Table   4 ). No significant difference in OS was seen by TTS among the ER+ (p=0.085) and ER-DCIS patients (p=0.669), cT1N0 NET patients (p=0.129), or cT2N0 NET patients (p=0.538). In the primary surgery group, a slight decrease in OS was seen in both the cT1N0 group (OS 96.7% in the <60 days to surgery group versus 94.7% in the >120 days to surgery group, p<0.001) and the cT2N0 group (OS 92.6% in the <60 days to surgery group versus 90.8% in the >120 days to surgery group, p=0.046).

Among patients with DCIS and among those with cT1-2N0 disease undergoing primary surgery, mastectomy rates increased with longer TTS (e.g. ER+ DCIS: 23.9% in the <60-day group versus 49.1% in the >120-day group; ER-DCIS: 37.2% in the <60-day group versus 57.1% in the >120-day group, p<0.001 for both). In the NET groups, however, mastectomy rates overall decreased by time, with the clearest trend in the cT2N0 NET group (57.7% in the <60day group versus 30.3% in the >120-day group, p<0.001) (Figure 3 ).

Oncologic surgery triage recommendations during the COVID-19 pandemic were based on best available evidence, but admittedly, as unprecedented circumstances forced unconventional practices, some extrapolations from existing data were necessary. Questions thus remain regarding the possible effect of the proposed delay strategies on oncologic outcomes. Our study found that on adjusted analyses, surgical delays of >120 days were associated with pathological upstaging in patients with DCIS but not in those with invasive disease. In DCIS patients and cT1-2N0 patients treated with NET, no survival differences were noted by TTS.

The anxiety of non-operative management of DCIS stems from known sampling error on core biopsy with pathological upstaging rates ranging from 10-30% at the time of surgery. 2 15 , these trials are enrolling highly selected patients and have yet to report their results. In addition, retrospective data have shown that, in patients meeting LORIS criteria, upstage rates at the time of surgery may be 7-20%. 16, 17 The prospect of leaving patients with undiagnosed and untreated invasive disease may thus engender discomfort in surgeons and patients alike.

The association between pathological upstaging and TTS in DCIS patients has previously been studied in the NCDB, with results consistent with ours, although patients were not stratified by ER-status. 2 The possible mitigating effect of NET on disease progression in ER+ DCIS has been demonstrated in a small series, 18 and was part of the recommended delay strategies during the pandemic. While there were too few DCIS patients on NET to render an adequate analysis in the current study, taken together, these data suggest that initiation of NET in patients with ER+ DCIS is a reasonable delay strategy. For patients with ER-DCIS in whom NET is not a viable option, the consequences of leaving disease in place for longer periods of time remains unclear.

Our findings are similar to a previous single-institution study that demonstrated a significantly higher upgrade rate among patients with ER-DCIS, 17 although it is unclear to what extent this phenomenon is driven by grade versus ER-status alone.

A previous study has suggested that longer TTS in DCIS patients may have a small, but statistically significant impact on OS. 2 This is likely mediated by the increased rates of invasive disease found on excision, although a previous analysis of SEER data suggests that breast-cancer specific mortality can be observed even in women who never have an invasive cancer diagnosis. 19 The lack of survival difference by TTS in our analysis may be due to short follow-up time and to the fact that we did not separate the upstaged patients from the patients with pure DCIS on final pathology. Given that the clinical question during the pandemic applied to patients in limbo between their DCIS diagnosis and surgical intervention, our finding that OS does not differ by TTS in both ER+ and ER-disease answers a different question than addressed by previous studies.

For patients with early-stage, ER+ breast cancer, NET is not currently widely used in the U.S. 20, 21 Similar in-breast tumor response rates have been noted in patients undergoing NET as compared to those undergoing neoadjuvant chemotherapy, 5 with 50-80% of women seeing partial or complete in-breast responses. 6, 22 While patients with cT1N0 disease were included in studies of primary endocrine therapy alone, which examined the difference in survival between older women undergoing primary endocrine therapy versus surgery and endocrine therapy, [8] [9] [10] NET has primarily been explored in patients with stage II-III disease in whom the intent was to downstage the primary tumor. 5 As such, the NET population in the NCDB, especially those with clinical T1 disease included in this study, represents a highly selected group. As our multivariable analysis shows, there are specific patient characteristics (i.e. older age, higher Charlson comorbidity index, not having private insurance) and disease characteristics (lower grade and having a cT2 tumor compared to a cT1 tumor) that were associated with a higher likelihood of receiving NET. The bias toward older patients with more comorbidities is not surprising, as NET studies have demonstrated the possibility of favorable tumor response with a more favorable toxicity profile than chemotherapy, 5 but does limit the applicability of our findings to the wider population affected by the COVID-19 surgical delays.

The lack of association between TTS and pathological upstaging in the NET group in our study is to be expected given the tumor response rates reported in previous NET studies, and supports the recommendations made by the COVID-19 Pandemic Breast Cancer Consortium.

The absence of a survival difference by TTS is also consistent with the lack of difference in OS found in the primary endocrine therapy trials. [8] [9] [10] In addition, majority of patients with cT2N0 disease were downstaged on final pathology. While the absolute number of patients is small, there may be some positive, albeit unintended, effects of this particular COVID strategy.

The relationship between TTS and pathological upstaging in patients with invasive breast cancer has been mixed. One modeling study in pregnant patients showed an association between TTS and an increased risk of positive nodes, with a three-month delay in surgery carrying an associated 2.6% increase in risk of positive lymph nodes. This has not been validated in an actual patient population. 3 In a population of clinically node-negative patients with early-stage breast cancer treated at the MD Anderson Cancer Center, TTS was not associated with pathologically positive lymph nodes on adjusted analyses. 4 Survival analyses have similarly reported mixed results, with some demonstrating a statistically significant association between TTS and decreased survival, [23] [24] [25] and others finding no such association. [26] [27] [28] Our analysis demonstrated a slight decrease in OS (approximately 2%) at a median follow-up of 40 months in patients who underwent primary surgery >120 days after diagnosis compared to those who underwent surgery within the first 60 days. Although a survival difference may be surprising in early-stage disease, this is consistent with a SEER/NCDB analysis from Bleicher et al, which found that TTS was associated with lower OS in patients with stage I/II disease, but not with stage III disease. 24 While we were able to adjust for certain patient, disease, and treatment factors, there are likely unmeasured factors underlying delays in treatment in this population, and that may be responsible for the slight decrement in OS. For instance, previous studies have noted that cohorts who undergo surgery further out from the time of diagnosis have higher proportions of Medicaid, uninsured, black, Hispanic, and lower-income patients. 25 In addition, among a cohort of Medicaid patients in North Carolina, differences in survival by time to treatment were noted not among early-stage patients, but among late-stage patients. 23 The relationship between survival and time to treatment may thus be significantly modified by socioeconomic and disease factors. Yet as increased TTS during the COVID-19 pandemic was driven by different factors, the small OS difference may not hold true when outcomes of these patients are analyzed in the future.

Unmeasured factors likely also underlie the association between TTS and the extent of breast surgery. The increase in mastectomy rates by TTS in the DCIS and primary surgery groups may not be linked to extent of disease; rather it may be a factor as simple as surgical scheduling that accounts for the greater proportions of mastectomies among patients undergoing surgery >60 days after diagnosis. Reconstruction, although not explored in our current analysis, has previously been associated with longer TTS. 4, 24 Extent of breast surgery in early-stage disease is also subject to patient preference, with a variety of non-disease-related factors driving a patient's decision to undergo mastectomy. [29] [30] [31] Our study has several limitations. First, as previously mentioned, the applicability of our findings is limited given that that populations suffering from delays in surgical therapy and who were selected for NET in this retrospective analysis are more select then the patients who have experienced a surgery delay during the pandemic. We would assert, however, that these are the best data currently available to study the possible outcomes of oncologic surgical delays. Second, in order to take advantage of the most current variables in the NCDB (e.g. HER2 status) and

given that NET use in the U.S. has only recently begun to be more widely adopted, our analysis was limited to 2010-2016, rendering our follow-up time relatively short. Third, using the AJCC 8 th edition prognostic staging allowed us to more accurately judge rates of meaningful (i.e. prognostic) differences in upstaging, but the pathological staging system does require more known data points (i.e. tumor grade, nodal status, HR-status, and HER-2 status). As such, not all the invasive cancer patients could be definitively pathologically staged. Finally, adherence to endocrine therapy cannot be assessed in the NCDB; this is a significant issue in breast cancer patients on endocrine therapy, which can influence OS. 32 Due to the retrospective nature of the NCDB, however, our reported survival data likely captures a "real-world" population of adherers and non-adherers alike.

In this analysis, surgical delays of >60 days were associated with pathological upstaging in patients with DCIS but not in those with invasive disease. No survival differences in patients with DCIS or early-stage ER+ positive breast cancer on NET were noted by time to surgery.

While the applicability of these data to the patients experiencing surgical delays during the COVID-19 pandemic is limited, surgeons and patients may find some reassurance in these findings, as these two groups represent patients significantly affected by the surgical triage recommendations of the COVID-19 Pandemic Breast Cancer Consortium. Future study of outcomes of patients treated during this time will be required to determine the actual impact of COVID-related surgical delays and delay strategies. ALND, axillary lymph node dissection; BCS, breast conserving surgery; DCIS, ductal carcinoma in situ; ER, estrogen receptor; N/A, not applicable; pT, pathological tumor category; pN, pathological nodal category; SLNB, sentinel lymph node biopsy. 

Recommendations for Prioritization, Treatment and Triage of Breast Cancer Patients During the COVID-19 Pandemic

Preoperative Delays in the Treatment of DCIS and the Associated Incidence of Invasive Breast Cancer

Breast cancer during pregnancy: quantifying the risk of treatment delay

Delays in primary surgical treatment are not associated with significant tumor size progression in breast cancer patients

Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis

Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031

Annual Hazard Rates of Recurrence for Breast Cancer During 24 Years of Follow-Up: Results From the International Breast Cancer Study Group Trials I to V

Late follow-up of a randomized trial of

Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial

Surgery, with or without tamoxifen, vs tamoxifen alone for older women with operable breast cancer: cochrane review

Breast Cancer-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual

Ductal carcinoma in situ at core-needle biopsy: meta-analysis of underestimation and predictors of invasive breast cancer

Feasibility of a prospective, randomised, openlabel, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ -The LORD study

Addressing overtreatment of screen detected DCIS; the LORIS trial

The COMET (Comparison of Operative versus

trial: a phase III randomised controlled clinical trial for lowrisk ductal carcinoma in situ (DCIS)

Do LORIS Trial Eligibility Criteria Identify a Ductal Carcinoma In Situ Patient Population at Low Risk of Upgrade to Invasive Carcinoma?

Surgical Upstaging Rates for Vacuum Assisted Biopsy Proven DCIS: Implications for Active Surveillance Trials

Phase II Single-Arm Study of Preoperative Letrozole for Estrogen Receptor-Positive Postmenopausal Ductal Carcinoma In Situ: CALGB 40903 (Alliance)

Breast Cancer Mortality After a Diagnosis of

Ductal Carcinoma In Situ

Trends in Neoadjuvant Endocrine Therapy Use and Impact on Rates of Breast Conservation in Hormone Receptor-Positive Breast Cancer: A National Cancer Data Base Study

Hormone Receptor-Positive Breast Cancer by Initial Treatment Approach

Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: A multicenter trial

Effect on survival of longer intervals between confirmed diagnosis and treatment initiation among low-income women with breast cancer

Time to Surgery and Breast Cancer Survival in the United States

Time to Treatment: Measuring Quality Breast Cancer Care

Delays in time to treatment and survival impact in breast cancer

Effect on survival of delays in referral of patients with breast-cancer symptoms: a retrospective analysis

Delays in treatment in the cancer services: impact on cancer stage and survival

Factors influencing the surgery intentions and choices of women with early breast cancer: the predictive utility of an extended theory of planned behaviour

A prospective comparison of younger and older patients' preferences for breast-conserving surgery versus mastectomy in early breast cancer

Factors influencing surgical treatment decisions for breast cancer: a qualitative exploration of surgeon and patient perspectives

Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer

ER, estrogen receptor; NET, neoadjuvant endocrine therapy