key: cord-1000912-5w44o3zc authors: Di Lena, Élise; Hopkins, Brent; Wong, Stephanie M.; Meterissian, Sarkis title: Delays in Operative Management of Early-Stage, Estrogen-Receptor Positive Breast Cancer During the COVID-19 Pandemic – A Multi-Institutional Matched Historical Cohort Study date: 2021-10-22 journal: Surgery DOI: 10.1016/j.surg.2021.10.033 sha: d39fd07a6b304aa00e99be4919b1f871c9ddde53 doc_id: 1000912 cord_uid: 5w44o3zc BACKGROUND: During the COVID-19 pandemic, guidelines recommended that breast cancer (BC) centers delay estrogen-receptor positive (ER+) BC surgeries with neoadjuvant endocrine therapy (NET). We aimed to evaluate pathological upstaging of BC patients affected by these guidelines. METHODS: Female patients with stage I-II BC receiving NET were prospectively identified and were matched to a historical cohort of stage I-II ER+ BC patients treated with upfront surgery ≤35 days. Primary outcomes were pathologic T- and N-upstaging vs clinical staging. RESULTS: After matching, 28 NET and 48 control patients remained. Median age in each group was 65 (p=0.68). Most patients (78.6% and 79.2%) had invasive ductal carcinoma with a clinical tumor size of 0.9cm vs 1.7cm (p=0.056). Time to surgery was 68 days in the NET group and 26.5 days in the control (p<0.001). 23 NET patients (82.1%) had the same or lower pT-stage compared to 31 (64.5%) control patients (p=0.115). Only 3 (10.7%) NET patients had increased pN-stage vs 14 (29.2%) control patients (p=0.063). CONCLUSION: Despite 2.5-times longer delays, patients with early-stage ER+ BC receiving NET did not experience pathologic upstaging during the COVID-19 pandemic. These findings may support the use of NET in similar patients if delays to surgery are projected. In March 2020, the province of Quebec, Canada declared a public health emergency due 65 to the SARS-CoV-2 (COVID-19) pandemic 1 . Similar to elsewhere in the world 2 , extraordinary 66 measures were taken to offload hospitals and better accommodate the influx of patients suffering 67 from COVID-19 3 . One such measure was to limit elective operations to those which were most 68 urgent or life-threatening and to reassign operating room staff to COVID floors and intensive care 69 units (ICUs) 4 . As part of this effort, federal and provincial, recommendations were to postpone 70 surgeries if necessary for early-stage (stage I or II) estrogen-receptor positive (ER+), human 71 epidermal growth factor receptor 2 negative (HER2-) breast cancers (BCs) with neoadjuvant 72 endocrine therapy (NET) until regular operative volume could be resumed [5] [6] [7] [8] [9] . 73 ER+ BCs continue to be the most commonly diagnosed subtype of BC, making up roughly 74 80% of new diagnoses 10 . For early-stage ER+ BC, standard of care includes upfront surgery 75 (partial or total mastectomy with or without axillary staging), followed by adjuvant endocrine 76 therapy with or without adjuvant radiotherapy and chemotherapy 11 . Use of NET in these patients 77 is usually reserved for patients with large or locally advanced tumors which can be converted to 78 breast conserving surgery with the use of NET, or as primary endocrine therapy for elderly patients 79 or those with significant comorbidities prohibiting operative intervention [12] [13] [14] [15] . The data are mixed, 80 but most studies have demonstrated that use of NET in large or locally advanced tumors is 81 equivalent or superior to use of neoadjuvant chemotherapy in postmenopausal patient populations, 82 though this remains controversial 16, 17 . However, intentional use of NET in early-stage ER+ BCs 83 was not standard of care prior to the pandemic and there are therefore limited data supporting its 84 use or demonstrating its effect on pathological upstaging in this patient population 9, 12 . Given this, 85 when the new guidelines took effect, we aimed to prospectively identify patients affected by these 86 J o u r n a l P r e -p r o o f guidelines at two referral-based breast cancer centers to evaluate the impact of this treatment on 87 their pathological staging. Study population 90 Prior to beginning the study, institutional ethics review board approval was obtained at 91 both institutions. Inclusion criteria were all female patients with early-stage (stage I-II), ER+ BC. final pathology were also excluded as it would be impossible to determine whether this was due 100 to pathologic complete response of the invasive tumor or rather to the entire tumor being removed 101 during the biopsy process. Identical inclusion and exclusion criteria were used to select those who 102 received NET due to operative delays during the pandemic. To identify patients for the historical control group, a prospectively maintained breast 104 cancer database from one of the two participating institutions was queried. Two-hundred patients 105 were randomly selected from a group of patients seen in the breast center's clinic between 2010-106 2013. Patients included in the historical cohort had to have stage I-II ER+ breast cancer and 107 undergo upfront surgery. Identical inclusion and exclusion criteria were used to select patients in 108 the historical control group. To eliminate bias from prolonged delays to surgery in the historical 109 J o u r n a l P r e -p r o o f control group, only patients who underwent surgery in 35 days or less from the date of diagnosis 110 were included in the matching process. 112 Electronic medical records were used to collect demographic, clinical, pathologic, and 113 radiologic data, as well as data specific to each patient's NET treatment if applicable. defined as tumors which were ER+ and with 50% or more progesterone expression (PR+). Luminal 125 B was defined as ER+ and less than 50% PR+. The primary outcomes of interest were changes in pathological T-and N-staging (pT and 127 pN) compared to pre-treatment clinical-radiologic T-and N-stages (cT and cN). grade, tumor biology, and cT-stage, use of NET decreased the odds of T-upstaging (OR 0.16, 95% 181 CI 0.03-0.82), but had no effect on N-upstaging, meaning that patients who received NET were 182 84% less likely to demonstrate T-stage upstaging during the peri-operative period compared to 183 patients who did not receive NET. Similarly, maximum size on imaging also increased the odds 184 of T-upstaging 3.28-fold (95% CI 1.00-10.7) after matching, while having no effect on N-185 upstaging (Table 3) . The COVID-19 pandemic put unprecedented stress onto healthcare institutions which were 188 often already stretched thin prior to the onset of the pandemic. In order to free up healthcare 189 personnel to work in ICUs and on COVID floors as well as to limit exposure of patients and 190 personnel to carriers of the disease, many institutions across the globe were forced to improvise 191 and attempt novel approaches in disease treatment 2, 3 . From telehealth to transfers of operative care 192 to institutions with less COVID burden, surgery was no exception, and delaying care for patients 193 with the most common but least aggressive BC subtype made intuitive sense. The hope was that 194 treating these patients with NET for variable periods of time would allow delay of their surgeries 195 until the worst of the pandemic was over without clinical repercussions 5-9 . 196 The data supporting this approach is limited and use of NET in ER+ BC remained limited 197 prior to the pandemic 12 . Use of primary endocrine therapy as sole therapy has long been an option 198 in elderly or comorbid patients who cannot undergo surgery, though long-term local control is There was also a significant discrepancy between the delay to surgery when compared to 257 the duration of NET (median delay to surgery of 68 days vs median duration of NET of 33.5 days), 258 which could possibly be explained by two factors. First, the date of diagnosis was pre-emptively 259 defined as the date of the first positive biopsy to avoid bias in assigning the date of diagnosis 260 between the NET and historical groups. This led to discordance between the date of diagnosis and 261 the date that the patient first met with their treating surgeon. Second, it is possible, especially at 262 the beginning of the pandemic, that physicians did not anticipate significant delays to surgery and 263 therefore only began NET several days/weeks after initially meeting with the patient and 264 consenting them for surgery. Administration of NET for this short of a duration is only beginning 265 to be studied 21, 22 ; it is therefore unclear whether this short course had any role in preventing disease 266 progression or whether this lack of progression is inherent to the indolent nature of these types of 267 tumors. However, some preliminary data does support that the tumor biology may already begin 268 to be altered after such as short a treatment course as 4 weeks 21, 22 . The true effect of short-course 269 J o u r n a l P r e -p r o o f NET would be better elucidated in a study comparing patients who received NET during this 270 period to patients who experienced similar delays to surgery but did not receive NET. Beyond the pandemic, these data support the safety of offering NET to patients with early- In conclusion, though use of NET in early-stage ER+ HER2-breast cancer remains limited, 280 this study demonstrates that patients who received NET during the COVID-19 pandemic as a risk-281 mitigation strategy while their surgeries were delayed faired no worse than historical controls in 282 terms of T-and N-upstaging despite over 2.5 times longer delays to surgery. As we emerge from 283 the pandemic era, these findings may support use of NET for early-stage ER+ tumors when the 284 treating team anticipates significant delays to surgery. An alternative conclusion from this research 285 may be that the traditionally quoted 28-day delay from diagnosis to surgery could be overly 286 conservative when considering the tumor biology of these early breast cancers. This would also 287 benefit from being studied in a prospective multi-institutional study. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f surgery because they met with them in early March, for example, and then called the patients at home and explained NET to these patients. So that's the second element that may explain the discrepancy between the 73 days and the 34 days in our NET group. Now, whether or not this was long enough for NET to actually have an impact is kind of unknown in this case. As you mentioned, specifically NET for a downsizing of tumors is given for four months or more in most patients. In our case, it was much shorter than that, as you mentioned. Whether or not these patients didn't have upstaging because they received NET remains a little bit unknown in this scenario. The second question that you had was the duration -the delays to surgery in the historical control. The objective of our study was really to determine whether or not patients during COVID saw their tumors be upstaged or had poor outcomes pathologically due to the delays to surgery during the COVID pandemic. We didn't actually want to compare patients to historical controls who had significant delays. We wanted to compare them to the standard of care. That's why we picked the 35 days. I agree, though, that it's an interesting idea to look back and try to find patients who had significant delays in the past and compared those patients, but matched them for delays to surgery and compared whether or not those patients saw significant upstaging or not during that time period and to determine whether NET had a protective effect in these patients. But we would have to go back and collect additional data to determine this. Finally, to address your third question on the takeaway points from this data, I think there are two ways to interpret this data, and I'm not sure which is right. One possible explanation is that NET was indeed protective even if it was given for a short period of time. As you mentioned in your first question, this was really a short period of time and no one has really evaluated the use of NET for just a month to know whether or not that this actually had an impact on tumor downsizing or at least preventing progression of tumors. I think by, like you mentioned, matching to patients who had significant delays to surgery and didn't receive NET, that would be an interesting way to answer that question or to conduct a prospective RCT looking at those two kinds of patient populations. Another possible takeaway from this study, I think, is that perhaps we're overly conservative in our guidelines that recommend for operating on these patients within a month of diagnosis. If you think about the tumor biology of these small, luminal A type tumors, perhaps they never would have progressed in our 70 or so days. So maybe in two months and a half, they don't actually have that high likelihood of progressing and that explains our results, in which case perhaps we should change our guidelines and not be overly nervous about delaying care for these patients. And that's kind of the impression that was given in that survey, in the 2001 survey of physicians during the COVID -surgeons during the COVID-19 pandemic who were quite comfortable delaying their patients to OR by up to two months without treating them with NET. Maybe this is already a general impression among surgeons that's not really reflected in the data. But, again, these small, observational studies often raise more questions in the answer. I think that to adequately answer the questions, we would need proper prospective large RCTs. J o u r n a l P r e -p r o o f DR. FAAIZA VAINCE (Loyola Medical Center): I have two brief questions. Did you guys utilize Oncotype at all in determining whether this was somebody that needed to be ushered to surgery sooner than later prior to putting them on the endocrine treatment? That is actually what panned out for us during the early onset of the pandemic in determining whether we needed to usher somebody to surgery, and in our case, we did not stop doing those surgeries, or whether to delay it, particularly if the patient had reservations about being operated on during the pandemic. My other question is, can you comment on what the pitfalls might be, if there are any, in putting somebody on endocrine treatment if there are delays, for whatever reason, anticipated? DiLENA: Regarding Oncotype, yes, so we did collect the data. In our whole cohort of 30 patients, there were, I don't want to say an exact number, but I think there were less than ten patients who actually had an Onotype DX that was performed. We perform them quite selectively at our institution. Typically, a multi-institutional tumor board has determined whether or not a patient needs Oncotype DX, and usually it's actually after the surgery, so not under biopsy. Not initially prior to their surgery. This wasn't routinely performed for patients and the surgeons wouldn't have known the Oncotype DX routinely before deciding whether or not the patients would go to surgery. I do think that's an interesting idea, trying to profile these tumors and know whether or not they're more proliferative as kind of a guideline of whether or not to operate on patients. Your second question was the potential pitfalls of putting patients on NET. I think that it's required careful monitoring, so we know that a certain subset of patients will progress on NET, and I think that carefully monitoring those patients is usually the standard of care, especially when you're using NET to downsize tumors. The issue, of course, was that patients were really scared to come to the hospital, and I don't think that it would have been feasible to routinely perform ultrasound during this period. Of course, like going forward in a non-pandemic world, then I think that it becomes more feasible to monitor patients with imaging if we're going to do longer term NET. The other potential pitfall, I would think, would just be the 5X profile of the endocrine therapy, but this is the same as for adjuvant therapies. 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The importance of this study is that it highlights that patients treated with neoadjuvant endocrine therapy in this context did not see their tumors upstaged despite 2.5 times longer delays to surgery than the matched historical control group, suggesting that neoadjuvant endocrine therapy may be a viable option for patients with early-stage, estrogen-receptor positive breast tumors who have foreseeable delays to surgery. DR. ZAHRAA AL-HILLI (Cleveland Clinic): The COVID-19 pandemic has posed a unique set of challenges for breast cancer screening and patients diagnosed with the disease. And certainly, reorganization of breast services meant that a number of patients diagnosed with hormone receptor positive breast cancer were offered treatment with neoadjuvant endocrine therapy during delays in surgery. The data presented by the authors adds to a growing body of literature on neoadjuvant endocrine therapy and may give reassurance for patients most impacted by treatment delays during the pandemic.I have three questions for the authors. First, the duration of treatment with neoadjuvant endocrine therapy in the studies is perhaps too short to demonstrate a change in tumor size. Data, including that from clinical trials on neoadjuvant endocrine therapy, included patients treated for an average of four months or longer. So the impact of shorter treatment duration remains unclear. Can you comment on the duration of treatment with neoadjuvant endocrine therapy and how this could have impacted the results? Second, your study compares patients treated with neoadjuvant endocrine therapy to patients who underwent primary surgery in less than 35 days and without a delay. Did you consider having patients with a delay in time to surgery but not treated with neoadjuvant endocrine therapy as the control group?And, finally, what lessons from your study can we take with us to the post-COVID era? Do you recommend that neoadjuvant endocrine therapy be considered for patients experiencing delays for other reasons, such as further workup or medical optimization prior to surgery? DR. DiLENA: Thank you, Dr. Al-Hilli for your thoughtful questions. For the first question regarding the duration of NET, I agree with you the duration of NET was a little bit short in our NET group. So just to explain this a little bit. Our delays to surgery were, in fact, two and a half times longer in our NET group compared to our historical control. But our duration of NET treatment was only 34 days. This can be explained by a couple of factors. First is that we used to standardize our date of diagnosis, we used the date of the first positive biopsy as the date of diagnosis for all patients across both cohorts. Obviously, this would lead to a delay between the date of diagnosis and the date that the patient first met with the surgeon. This is one element that explains this discrepancy. The second element is that, and this is more hypothetical, that perhaps the surgeons, when they first met with patients and consented them for surgery, didn't actually know that there would be significant delays to surgery at that time. And this, I am speaking a little bit anecdotally, but in collecting the data, we observed that -this is the case for several patients, so basically the surgeon would meet with them, consent them for surgery, and then only realize afterwards that there would be significant delays to