Delays in the treatment of breast cancer matter, but not as much “as we and our patients typically assume,” Richard J. Bleicher, MD, FACS, informed participants at the 22nd Annual Lynn Sage Breast Cancer Symposium.1 Some of these delays are unavoidable and others are tradeoffs that must be made to obtain more information and provide better treatment.
In two separate analyses of data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database and the National Cancer Database (NCDB), comprising a total of more than 200,000 patients, “the difference in overall survival between the times from diagnosis to surgery of under 30 days vs over 90 days, when adjusting for patient, tumor, and treatment factors, was about 3% to 4%,”2 Dr. Bleicher reported. “A benefit of 3% is probably a reasonable threshold,” he noted, so although there is not yet a standard for the time from diagnosis to surgery, delays of up to 90 days “would be reasonable.”
Richard J. Bleicher, MD, FACS
Chemotherapy is typically recommended “within 4 months of diagnosis,” Dr. Bleicher added, and the standard for radiation therapy is to initiate it within 1 year of diagnosis for patients who are receiving chemotherapy. For patients who are not receiving chemotherapy, radiation “within 20 weeks of surgery, or about 8 months from diagnosis, is probably best.” Endocrine therapy should be given to eligible patients within a year, he added.
Dr. Bleicher is Professor of Surgical Oncology, Leader of the Breast Cancer Program, and Director of the Breast Fellowship Program at Fox Chase Cancer Center, Philadelphia. The Lynn Sage Breast Cancer Symposium, which went virtual this year, is hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
Inextricable Delays
A review of SEER-Medicare data from 72,586 patients with breast cancer found that the average time between first physician visit and first therapeutic surgery “was about 1.5 months,” Dr. Bleicher reported.3 This study also “evaluated how the things that we do in our own workups of breast cancers contribute to the timing of treatment. When adjusting for other factors, pretty much everything we do contributes to delays,” Dr. Bleicher noted.
“Each type of preoperative imaging contributes [to delays]. Preoperative biopsies do as well, with more invasive biopsy types adding to more overall time. Although a fine-needle aspiration adds 6 days, a core-needle biopsy adds 13 days, and an excisional biopsy, which requires operating room scheduling, contributes [to delays of] over 17 days,” Dr. Bleicher reported. “It is clear that the things we must do that are inextricable from the workup do contribute to delays in the time to treatment.”
Procedures that are not required but that are considered “highly desirable” can also cause delays. “The best example would be having surgery, medical oncology, and radiation oncology all see the patient preoperatively in a multidisciplinary fashion,” Dr. Bleicher said. A review of 88,865 patients found that if physicians from those three specialties all saw the patient preoperatively on the same day, it added 6.8 days to the interval between diagnosis and surgery; however, if they saw the patient on different days, it added 12.6 days.4
There are other factors “in the patient’s journey from diagnosis to treatment that are not within our control that cause delays,” Dr. Bleicher noted, such as transferring care between institutions. That can increase time to treatment by 7.3 to 9.8 days.5
‘Stunned’ by DCIS Data
The combined seer-medicare and NCDB data showed “a consistent decline in survival the further out from diagnosis surgery was performed,” Dr. Bleicher said. “For every month in delay between diagnosis and surgery, there is about a 9% to 10% relative decline in overall survival and a 26% relative decline in disease-specific survival.” (He stressed that these declines were relative.)
“We expected no relationship between treatment delays for ductal carcinoma in situ (DCIS) and survival. However, we were stunned to find that, in [approximately] 140,000 patients, the delays between diagnosis and surgery for DCIS did, in fact, make a difference, albeit a very small one,” Dr. Bleicher said. A study of patients with clinical DCIS, identified through the NCDB, reported that adjusted 5-year survival estimates were 96.2% for time to surgery of 30 or fewer days, 95.5% for 91 to 120 days and 93.4% for more than 120 days.6 These differences are “significant but small,” he remarked.
“If a patient is diagnosed with DCIS on core biopsy, there is a similar decline [in survival] of about 7% per month [of delays], whether invasion is found on excision or not,” Dr. Bleicher stated. Overall, 5-year survival estimates were 96% for those without invasion vs 95% for those with invasion. “The decline in survival is probably similar because those without invasion likely have occult invasion that we just haven’t seen, and for those where invasion is found, the median invasive size in such cases is a T1a lesion at only 5 mm,” Dr. Bleicher commented.
“Most concerning—potentially, at least—was a significant increase in the likelihood of finding invasion on pathology the further out from diagnosis that the DCIS was excised. If [excision] was done within 30 days, there was an 11% chance of finding invasion, increasing to 15% when over 4 months,” Dr. Bleicher reported. “If this phenomenon of increasing invasiveness with longer delays holds true for most patients, then our DCIS observation trials, which essentially represent infinite delay because we are not operating, are going to require careful long-term follow-up to make sure outcomes are not compromised by that nonoperative management,” he continued. “My personal opinion is there are probably two cohorts of patients with DCIS that we will ultimately need to distinguish: those whose DCIS doesn’t ever become clinically significant, and patients whose DCIS does develop invasion and puts them at risk.”
Phenotypes Affected Equally
In a study of 351,087 patients with noninflammatory breast cancer who did not receive neoadjuvant chemotherapy, Dr. Bleicher and his co-investigators found that after adjusting for patient presentation, tumor, and treatment factors, the effect of treatment delay on survival did not differ among different breast cancer phenotypes.7 “There is a 9% relative drop in overall survival per month of delay between diagnosis and surgery for all breast cancer types,” he noted. “There also was no significant difference for the interval between surgery and chemotherapy and for the entire interval for diagnosis through surgery to chemotherapy.” The differences in absolute survival declines between triple-negative breast cancer and other phenotypes are so small “that there is no statistical or clinical difference between them,” Dr. Bleicher said.
The researchers concluded that although neoadjuvant therapy “is sometimes advocated solely to avoid treatment delays, this study does not suggest a greater surgical urgency for triple-negative breast cancers compared with other breast cancer phenotypes.”
“Neoadjuvant chemotherapy doesn’t seem to start treatment quicker, nor does it get patients through their treatment more efficiently,” Dr. Bleicher stated, citing results from a study of 155,606 patients with clinical stage I to III breast cancer.8 After adjustments were made for stage and other factors, women who received neoadjuvant chemotherapy actually had slightly longer times to begin treatment, 36.1 vs 35.4 days. “There are reasons to give many patients with triple-negative breast cancer neoadjuvant chemotherapy,” he said, “but speed or rapidity of treatment is not one of them.”
Getting Patients to Treatment
Getting patients to the operating room within 90 days of diagnosis seems to be “a reasonable expectation,” Dr. Bleicher said. In the United States, 98% to 99% of patients “get to operative therapy as their first modality within that time period. So, although there is no standard yet, 90 days is probably reasonable.”
There are time-dependent standards for other treatment modalities. For chemotherapy, it is within 4 months of diagnosis. With common chemotherapy regimens running from 12 to 24 weeks, “that leaves 8 weeks to do simulation and planning for radiotherapy, and that works well” for radiation to be performed within 1 year, the standard, unless patients aren’t getting chemotherapy, Dr. Bleicher noted. For patients not receiving chemotherapy, radiation “should be completed by about 8 months,” he added.
The standard for endocrine therapy, Dr. Bleicher said, is that it “should be done for eligible patients within a year. However, so far, there are no published data regarding the effect of delays on endocrine therapy [outcomes].”
DISCLOSURE: Dr. Bleicher reported no conflicts of interest.
REFERENCES
1. Bleicher R: Delay in breast cancer treatment: Is it harmful? 22nd Annual Lynn Sage Breast Cancer Symposium. Presented September 11, 2020.
2. Bleicher RJ, Ruth K, Sigurdson ER, et al: Time to surgery and breast cancer survival in the United States. JAMA Oncol 2:330-339, 2016.
3. Bleicher RJ, Ruth K, Sigurdson ER, et al: Preoperative delays in the US Medicare population with breast cancer. J Clin Oncol 30:4485-4492, 2012.
4. Churilla TM, Egleston BL, Murphy CT, el al: Patterns of multidisciplinary care in the management of non-metastatic invasive breast cancer in the United States Medicare patient. Breast Cancer Res Treat 160:153-162, 2016.
5. Bleicher RJ, Chang C, Wang CE, et al: Treatment delays from transfers of care and their impact on breast cancer quality measures. Breast Cancer Res Treat 173:603-617, 2019.
6. Ward WH, DeMora L, Handorf E, et al: Preoperative delays in the treatment of DCIS and the associated incidence of invasive breast cancer. Ann Surg Oncol 27:386-396, 2020.
7. Mateo AM, Mazor AM, Obeid E, et al: Time to surgery and the impact of delay in the non-neoadjuvant setting on triple-negative breast cancers and other phenotypes. Ann Surg Oncol 27:1679-1692, 2020.
8. Melchior NM, Sachs DB, Gauvin G, et al: Treatment times in breast cancer patients receiving neoadjuvant vs adjuvant chemotherapy: Is efficiency a benefit of preoperative chemotherapy? Cancer Med 9:2742-2751, 2020.
