Prolonged Time from Diagnosis to Breast-Conserving Surgery is Associated with Upstaging in Hormone Receptor-Positive Invasive Ductal Breast Carcinoma

Multivariable analyses of clinical T1N0M0 ductal breast carcinoma patients who received BCS as their first definitive treatment revealed that the preoperative period (TTS) was a significant predictor of disease progression in HR-positive patients, with 8% and 30% higher odds of T-upstaging at ≥ 61 and ≥ 91 days TTS, respectively, and 17% higher odds of N-upstaging at ≥ 91 days TTS. Studies demonstrating a positive association between TTS and mortality risk among patients with early-stage breast cancer,9,10 as well as a positive association between TTS and upstaging of DCIS,8,13 raised the question of whether a prolonged preoperative interval is associated with measurable disease progression. However, earlier studies have not shown an association between TTS and upstaging in invasive disease.11‐13 An institutional study enrolling clinically node-negative invasive breast cancer patients (n = 635) demonstrated no association between time from radiographic screening (mammography or sonography) to surgery (median 21 days, range 1–132 days) with tumor size or lymph node upstaging.11 Similarly, a comparison of serial sonographic images at the time of initial diagnosis and the day prior to surgery (median 31, range 8–78 days) among 323 unifocal invasive breast cancer patients concluded that time between diagnosis and surgery >30 days was not associated with tumor growth compared with time ≤ 30 days.12 This discrepancy may be attributable to several factors, including shorter median or range of TTS compared with our cohort (median 28 days in HR-positive and 27 days in HR-negative; range 8–180 days), differing classifications of TTS intervals, and inclusion of a broader range of disease (stage, histology, and HR status). A more recent study for the analysis of cT1-2N0 disease using the NCDB (n = 279,090) showed that TTS had no association with upstaging from clinical to pathologic prognostic stage after adjustment; however, a trend of increasing upstaging with prolonged TTS was seen among patients with cT1N0 disease in unadjusted analysis.13 One of the key differences in our study is the use of a selective cohort of anatomic cT1N0M0 ductal breast carcinoma patients who received BCS as their first definitive treatment. Since mastectomy is indicated for higher-risk disease (e.g. multifocal, multicentric, family history/genetics, etc.), patients who underwent mastectomy were excluded due to differing disease nature from those who receive BCS.13 In fact, mastectomy was a significant predictor of disease upstaging in other studies.8,13 Similarly, patients with non-ductal histology such as lobular carcinoma were excluded based on predicted ambiguity of radiographic tumor size measurement reported in lobular carcinoma in situ.13 Lastly, our cohort was categorized by TTS intervals of ≤ 30, 31–60, 61–90, and ≥ 91 days, with ≤ 30 days TTS as the reference category based on the observed statistically significant difference in overall mortality observed in each 30-day interval beyond ≤ 30 days TTS.9 Overall, our data highlight the importance of minimizing the preoperative period to avoid the potential risk of disease progression in HR-positive T1N0M0 ductal breast carcinoma.

Similar to upstaging trends reported in DCIS patients, our analysis recapitulated a positive association between upstaging and HER2 positivity, higher histology grade, and younger age in T1N0M0 ductal carcinomas.17‐20 Our multivariable analysis showed that the nipple/central portion of the breast is significantly associated with increased risk of upstaging relative to tumors located in the upper outer quadrant for HR-positive tumors, presumably due to the convergence of mammary ducts at the nipple-areolar complex.21 The high density of fibroglandular tissue in this region results in heightened radiographic opacity that poses a challenge for sensitivity of mammographic detection in retroareolar masses.21 Another clinically significant finding of our study was age-related differences in upstaging. This may be attributable in part to the higher prevalence of aggressive subtypes or higher breast density among premenopausal women.19,22 Breast Imaging Reporting and Data System (BI-RADS) category 4 and 5 disease (as opposed to category 3) is reported to be consistently and significantly associated with upstaging of DCIS to invasive breast cancer.6 Greater breast density, defined by a higher percentage of radiographically dense epithelial and stromal tissue in the breast as opposed to radiographically lucent adipose tissue, both decreases mammographic sensitivity for detecting breast masses and is an independent risk factor for breast cancer regardless of the method by which it is detected.23,24 A cross-sectional meta-analysis of over 11,000 women found that mammographic density decreased with increasing age in both premenopausal and postmenopausal women, with the greatest reduction in mammographic density occurring at the time of menopausal transition.25

During the coronavirus disease 2019 (COVID-19) pandemic, 15% of cancer patients reported that their inpatient surgical procedures had been affected.26 Given the concern over the potentially negative survival impact of excessive surgical delays, the COVID-19 Breast Cancer Consortium published guidelines for operative prioritization. T1N0 estrogen receptor (ER)-positive/HER2-negative patients are categorized into priority level C1 and recommended neoadjuvant endocrine therapy (NET) in the context of delayed operation27 based on the comparable efficacy and overall survival rate of NET to adjuvant endocrine therapy in the GRETA trial.28 A NCDB cohort study showed that postmenopausal women with cT2-4c ER-positive breast cancer (n = 2,294) treated with NET were 1.6 times more likely to undergo BCS.29 Similarly, Minami et al. recently demonstrated that in patients with cT1-2N0 breast cancer, NET use did not impact stage or overall survival, supporting its safe use as a means of delaying surgery in patients with ER-positive breast cancer during the COVID-19 pandemic.13 Additionally, randomized studies have demonstrated an overall response rate to NET of >50% and an NET-induced conversion rate to BCS of >30%.30‐32 The duration and type of NET have been suggested to affect the response rate.33 While the incremental benefit of NET is evident at a therapy duration of up to 8 months,32,34 studies of short treatment duration showed limited efficacy,35 as the response rate of breast cancer to NET is slow. The P024 trial, during which postmenopausal women with ER-positive stage II–III breast cancers (n = 228) underwent treatment with neoadjuvant letrozole or tamoxifen for 4 months prior to surgery, revealed a significantly higher overall response rate in patients treated with letrozole (55% vs. 36%).30,36 Despite efficacy in downsizing tumors and the favorable safety profile of NET,31,36 the rates of disease progression during NET range from about 5–25%,30‐32 partly due to molecular mechanisms that contribute to endocrine resistance.37‐40 Since the primary focus of randomized trials using NET has largely been to downstage clinical stage T2 or higher tumors,30,34,35 its effect on T1N0 breast cancer remains unknown. Since the current study focused on patients who underwent surgery as their primary cancer treatment and excluded NET-treated cases, our data are not generalizable to those who were treated with NET and experienced extended surgical delays during the COVID-19 pandemic. Further follow-up retrospective studies to evaluate the impact of NET on T1N0 HR-positive breast cancer patients using a dataset with capacity for data adjustment for NET responses will be critical in gaining insight into breast cancer management.

The current study has several strengths and limitations. The large cohort size, along with the ability to adjust for multiple tumor properties and demographic characteristics with exclusion of potentially confounding subpopulations, provides, for the first time, a valuable context for understanding of the association between surgical delays and measurable disease progression of both tumor size and nodal status in IDCs. To our surprise, after multivariable analysis, TTS-dependent upstaging remained significant in HR-positive patients, but not in HR-negative patients, even though the likelihood of T-upstaging among HR-negative patients was nearly double that among HR-positive patients (11.0% vs. 6.8%). Additionally, there was no interaction between TTS and HER2 status in any of the models, suggesting both luminal A (HR-positive/HER2-negative) and B (HR-positive/HER2-positive) subtypes are likely to be affected by a delay in surgery. In light of this insight, which seems opposed to current understanding of HR-positive disease as slow-proliferating and HR-negative disease as rapidly-proliferating,41,42 it is critical to address the mechanism underlying HR-specific TTS-associated upstaging. One main limitation includes the varying detection sensitivity43‐45 of radiographic images utilized for clinical staging. Accurate tumor size measurement by mammogram and sonogram remains a challenge, especially in dense breast tissue,46,47 lobular carcinomas,48 and lesions under the nipple/areolar complex.21 Since the type of imaging modality and BI-RADS score are unavailable in the NCDB, further investigation with such variables to address the ambiguity of radiographic imaging is necessary to further determine the contribution of TTS to upstaging. Additionally, although we used a clinically selective subpopulation for our analysis, characterized by small early-stage tumors, to substantiate TTS-associated upstaging of invasive breast cancer, this does not negate the possibility of TTS-associated upstaging in higher-stage disease or disease with non-ductal histology.

Overall, preoperative disease progression of clinical T1N0M0 ductal carcinoma patients was largely attributable to intrinsic tumor biology, including subtype, histology grade, and tumor location, and to demographic factors, including age, race/ethnicity, and comorbidities. However, TTS presented a modifiable factor that was significantly associated with both T- and N-upstaging among HR-positive clinical T1N0M0 ductal carcinoma patients, underscoring the importance of timely surgery.