Abstract
Background/Aim: Currently, several ongoing prospective studies are investigating the safety of breast surgery omission in patients with breast cancer who are exceptional responders to neoadjuvant chemotherapy. However, there is little information about the preferences of these patients regarding omission of breast surgery. Patients and Methods: We conducted a questionnaire survey to assess preferences regarding omission of breast surgery among patients with breast cancer who had human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors and good clinical response after neoadjuvant chemotherapy. Patients’ estimation of the risk of ipsilateral breast tumor recurrence (IBTR) after definitive surgery or breast surgery omission was also assessed. Results: Of 93 patients, only 22 (23.7%) said they would omit breast surgery. Under the scenario of omitting breast surgery, the 5-year IBTR rate estimated by patients who said they would omit breast surgery was significantly lower (median, 10%) than the rate estimated by patients who preferred undergoing definitive surgery (median, 30%) (p=0.017). Conclusion: The proportion of our surveyed patients who were willing to omit breast surgery was low. Patients who said they preferred to omit breast surgery overestimated the 5-year IBTR risk.
Neoadjuvant chemotherapy (NAC) for breast cancer has become the standard therapy not only for locally advanced cases but also for operable, early-stage breast cancer. Recently, owing to the advances in chemotherapy and targeted therapy, the rate of pathologic complete response (pCR) is reaching 60% among human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (1, 2). This finding has attracted physicians’ interest in “breast surgery omission” in reference to the ultimate breast-conserving therapy (3). Several ongoing worldwide prospective studies are investigating the safety of breast surgery omission in patients with breast cancer who are exceptional responders to NAC (4, 5). To date, however, these prospective studies have not provided sufficient safety data on omission of breast surgery.
In addition of the lack of safety data about breast surgery omission, a remaining problem for the introduction of breast surgery omission into clinical practice is the lack of information about the preferences of patients with breast cancer. In their commentary to an article about research into breast surgery omission, Caballero et al. stated that an important aspect of de-escalation strategies such as breast surgery omission is to listen to the patient’s perspective during the early stages of developing future clinical trials, and to understand more about the level of risk the patient is willing to accept if a radical treatment such as surgery is not performed (6). However, to our knowledge, there are no studies investigating patients’ preferences regarding omission of breast surgery when a pathologic response is achieved after NAC and patients’ perception about the risk of local recurrence or overall survival when they do or do not receive breast surgery.
To help health care providers understand the preferences of patients with breast cancer regarding omission of breast surgery, and to help in conducting future large-scale prospective trials on the omission of breast surgery and its future introduction into clinical practice, we investigated the preferences of patients with breast cancer regarding omission of breast surgery when a pathologic response is achieved after NAC, as well as patients’ perception about the risk of local recurrence or overall survival if they do or do not undergo breast surgery.
Patients and Methods
Participants were patients with early-stage breast cancer who visited one of six institutions in Japan as part of their regular postoperative follow-up between January 2022 and August 2022. Eligibility criteria were as follows: 1) patients with stage 1-3 breast cancer and HER2-positive or estrogen receptor (ER)-negative tumors; 2) patients who had clinical complete response (cCR) or clinical partial response (cPR) to NAC; cCR and cPR were defined using the Response Evaluation Criteria in Solid Tumors (7); 3) underwent definitive surgery after NAC between April 2012 and October 2021, and 4) patients with no evidence of recurrence at the time of participation. Patients who had known BRCA1 or BRCA2 mutation were excluded. This study was approved by each institutional review board. The study was conducted in accordance with the ethical principles laid down in the Declaration of Helsinki.
Consecutive patients who were eligible to participate in this study were directly approached by one of the investigators in an outpatient setting. If the patient showed an interest in the study, detailed information was provided; patients were then approached for enrollment. Respondents completed the questionnaire and posted it to Mie University Hospital or filled out a Google form. Respondents provided their consent via completion of the questionnaires.
Participants read a hypothetical clinical scenario, modified from those developed by Ishitobi et al. (8) (see https://docs.google.com/forms/d/1tu9z8kGhZroZwVz-04pHQnb77SnPS6NaDt8zshCGcrE/edit): “Imagine you were recently diagnosed with breast cancer and have received NAC. Your breast tumor has become markedly smaller after completion of NAC. You then see a specialist who recommends that you participate in a clinical trial regarding omission of breast surgery because the specialist determined that your breast cancer would be cured without breast surgery. If you participate in the trial, the morbidity of breast surgery can be avoided. However, there is a possibility that micro foci of breast cancer remain in your breast, which may lead to breast cancer recurrence. This could decrease the possibility of curing your breast cancer. Would you opt to omit breast surgery?” Each participant was to select their preference regarding breast surgery omission from among three response options: yes, no, or no preference. Each participant was then to circle all applicable reasons for their preference from among the following options: “To minimize breast deformity and surgical wounds”, “To reduce the risk of breast cancer recurrence as much as possible”, “To reduce the morbidity of treatment as much as possible”, “To do everything I can by myself”, “To reduce treatment costs as much as possible”, “To increase the possibility of curing breast cancer as much as possible”, “To avoid hospitalization for treatment”, and “Other reasons”. To assess participants’ perception regarding the risk of disease recurrence, participants were asked, “What do you think the chance is that you will have a recurrence of breast cancer in your breast within 5 years if you undergo definitive surgery?” Responses to this question were from 0% to 100%. For this question, we provided a reference value from a previous report (9), which stated that a percent likelihood of breast cancer recurrence of approximately 3% was considered acceptable and approximately 12% was considered unacceptable. The same question was asked for the scenario in which breast surgery is omitted. Finally, participants were asked about their perception regarding their likelihood of survival for 5 years after each breast cancer treatment.
We collected clinicopathologic data on included patients from the participating institutions. The following data were collected: age at diagnosis, date of birth, menstrual status at diagnosis, clinical tumor (T) status, clinical node (N) status, ER and HER2 status before NAC, NAC regimen, clinical tumor response, date of definitive surgery, breast surgical procedure, breast reconstruction, pathologic T status, pathologic N status, pathological tumor response, adjuvant chemotherapy, endocrine therapy, anti-HER2 therapy, radiotherapy to the breast or chest wall, boost radiation, radiotherapy to sites other than the breast or chest wall, and date of last visit. ER status was considered positive if immunohistochemical staining showed that more than 1% of cells tested were positive for the receptor. HER2 status was determined using immunohistochemistry, fluorescent in situ hybridization, or both. We defined HER2 positivity as a receptor over-expression staining score of 3+ in immunohistochemistry or gene amplification with an HER2/CEP17 ratio >2.0 in a fluorescent in situ hybridization assay.
Statistical analysis. The χ2 test was used to evaluate the correlation between patients’ preferences and clinicopathologic factors and between patients’ preferences and the reasons for their preferences. The Mann-Whitney U-test was used to evaluate the correlation between patient preference and perceived risk of ipsilateral breast tumor recurrence (IBTR) and overall survival. A p-value <0.05 indicated statistical significance. All statistical analyses were performed using IBM SPSS Statistics 28.0 (IBM Japan, Tokyo, Japan).
Results
A total of 142 patients were approached for the study, and 105 (73.9%) completed the questionnaire. Of these, nine patients were ineligible because their data could not be matched with their clinicopathologic data; one patient who was found to have BRCA1 mutation and two patients whose breast cancer subtype did not meet the eligibility criteria were excluded. Finally, 93 patients were included in this analysis. Patient characteristics are shown in Table I. The median patient age was 54 (21-76) years. Six (6.5%) patients had cStage 1 disease, 52 (55.9%) had cStage 2 disease, and 35 (37.6%) had cStage 3 disease. Forty-five (48.4%) patients had cCR and 48 (51.6%) had cPR. Thirty-eight patients (40.9%) were ER-positive/HER2-positive, 38 (40.9%) were ER-negative/HER2-positive, and 17 patients (18.3%) were ER-negative/HER2-negative. Thirty-four (36.6%) patients underwent breast-conserving surgery, and 59 (63.4%) underwent mastectomy.
Patient characteristics.
Patient preferences and reasons for preference. Of the 93 patients who completed the questionnaire, 22 (23.7%) said they preferred to omit breast surgery, 36 (38.7%) did not have this preference, 34 (36.6%) had no preference, and 1 (1.1%) patient did not respond to this question. The associations of patient preference for breast surgery omission with clinicopathologic factors are shown in Table II. Patient preferences were not associated with age, clinical stage, clinical or pathological tumor response, breast cancer subtype, or breast surgical procedure. The most frequently reported reason for breast surgery omission was “to minimize breast deformity and surgical wounds” (72.7%); the second most frequently reported reason was “to reduce the morbidity of treatment as much as possible” (68.2%) (both p<0.001) (Figure 1). Among patients who did not prefer to omit surgery, the most frequently reported reason for their preference was “to reduce the risk of breast cancer recurrence as much as possible”, (83.3%, p<0.001); the second most frequently reported reason was “to increase the possibility of curing breast cancer as much as possible” (63.9%, p=0.018).
Association of patient preference for breast surgery omission with various clinicopathological factors.
Respondents’ reported reasons for preferring or not preferring breast surgery omission.
Patients’ perception of IBTR and overall survival. Under the scenario of receiving definitive surgery, the 5-year IBTR rate estimated by patients who said they preferred to omit breast surgery was a median of 5% [interquartile range (IQR)=3-10)]; this was 7.5% (IQR=3-25) among patients who said they preferred definitive surgery (Figure 2A). There was no significant difference in the estimated 5-year IBTR rate between the two groups (p=0.120). However, under the scenario of omitting breast surgery, the 5-year IBTR rate estimated by patients who preferred to omit breast surgery was significantly lower [median, 10% (IQR=5-30)] than that among patients who preferred definitive surgery [30% (IQR=12.5-50), p=0.017] (Figure 2B). Regarding the estimated 5-year overall survival, there was no significant difference between the two groups for the scenario of receiving definitive surgery (90% in the group who preferred to omit surgery group vs. 80% in the group who preferred definitive surgery, p=0.117). Similarly, there was no significant difference between the groups for the scenario of omitting surgery (77.5% in the group who preferred to omit surgery group vs. 60% in the group who preferred definitive surgery, p=0.153).
Five-year ipsilateral breast tumor recurrence rate estimation according to patient preference for breast surgery omission A) under the scenario of breast surgery omission or B) under the scenario of receiving definitive breast surgery.
Discussion
To our knowledge, this was the first study to investigate patients’ preferences for omitting breast surgery among patients with breast cancer who had a clinical response to NAC. In this study, the proportion of participants who preferred to omit breast surgery was 23.7%. This result is in contrast with a previous study, in which most physicians expressed interest in investigating the omission of surgery for their patients with breast cancer who have pCR after NAC (3). There have been several reports of discrepancies in perceptions regarding breast cancer treatment between patients and their physicians. A typical example regarding these discrepancies is contralateral prophylactic mastectomy (CPM). The National Cancer Center Network and American Society of Breast Surgeons guidelines recommend CPM only for patients at high risk of contralateral breast cancer, such as BRCA1/2 mutation carriers and patients with a strong family history (10, 11). However, a previous report using Surveillance, Epidemiology, and End Results registry data demonstrated that most patients (68.9%) who received CPM had no major genetic or familial risk factors for contralateral breast cancer (12). Thus, it is important to consider that a gap exists in the perception of breast cancer treatment and risk of recurrence between physicians and patients.
In this study, patient preference for breast surgery omission was not associated with age, stage, clinical or pathological response, or breast surgical procedure. Although there was no significant difference, patients who received mastectomy without breast reconstruction had less preference for omitting breast surgery (31.4%) than those who received oncoplastic breast surgery (i.e., breast-conserving surgery with or without breast reconstruction, mastectomy with breast reconstruction) (47.8%). It is reasonable that patients who received oncoplastic breast surgery would prefer to omit breast surgery. However, because the lack of differences in this study might be explained by our small sample size, further studies are needed.
In this study, patient preference strongly depended on patients’ perceptions regarding omission of breast surgery. Patients who preferred to omit breast surgery felt that less-invasive surgery (i.e., less breast deformity and surgical morbidity) was important. However, patients who did not wish to omit breast surgery thought that minimizing the risk of recurrence was important. A study investigating perceptions regarding mastectomy among patients with breast cancer who had received unilateral or bilateral mastectomy reported that the most frequent reason for choosing mastectomy over breast-conserving surgery was minimizing the recurrence risk and was not associated with patient age; this finding is compatible with our study results (13).
In the present study, the estimated 5-year IBTR rate with omission of breast surgery was significantly lower among patients with a preference to omit breast surgery (median, 10%) than among those who did not have this preference (median, 30%). However, the median estimated 5-year IBTR rate of 10% among patients who wished to omit breast surgery was markedly higher than expected because we provided a reference value from a previous report on the questionnaire (9), in which a rate of approximately 3% was considered acceptable and approximately 12% was considered unacceptable. To date, there is only one prospective clinical trial investigating the safety of omitting surgery among patients who have an exceptional response to NAC (5). In that trial, there has been no IBTR among 31 patients with a median follow-up of 26.4 months. This result is quite promising; however, caution is needed owing to the small sample size and short follow-up period. Several studies have reported the IBTR or loco-regional recurrence rate among patients with triple-negative or HER2-positive tumors who achieve a pCR after NAC and breast-conserving treatment (9, 14, 15). In these studies, the 5-year IBTR and loco-regional recurrence rate was 0% to 4.5% (9, 14) and 0% to 2.6% (15), respectively, which is also lower than 10%. It was surprising that patients who preferred to omit breast surgery would accept a high rate of 10%; this finding provides an important insight for future clinical trials investigating breast surgery omission. We cannot rule out that our patients’ high survival estimates can be explained by the fact that these patients actually received surgery and did not omit breast surgery. Patient-reported outcomes from the ongoing prospective clinical trial investigating breast surgery omission are awaited (5).
The first limitation of this study is the small sample size. The second limitation is that to increase the number of patients enrolled, the study inclusion criteria were not limited to patients who had cCR or pCR and those who received breast-conserving surgery, although patients’ preference for breast surgery omission was not associated with clinical or pathological response and breast surgical procedure. Third, because participants in this study provided their consent via completion of the questionnaire, we could not compare clinicopathologic data between participants and non-participants. Fourth, we did not collect data associated with patients’ preference for breast surgical procedure, such as patient educational level, insurance type, marital status, or comorbidities (16). Finally, the lack of patient participation in the planning of this study is a limitation.
This study demonstrated that few patients with breast cancer who have a clinical response to NAC prefer to omit surgery, and that patients’ estimates of IBTR risk significantly depend on their preference regarding breast surgery omission. These findings may provide important implications for future clinical trials investigating breast surgery omission and its future introduction into clinical practice. However, further studies are needed.
Acknowledgements
The Authors thank Analisa Avila, MPH, ELS, of Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
The study was designed by Makoto Ishitobi. Data were collected by all Authors. All data were analyzed by Kaho Nakamura and Makoto Ishitobi and interpreted by all Authors. Makoto Ishitobi contributed to funding acquisition and supervision. Kaho Nakamura and Makoto Ishitobi drafted the manuscript. All Authors critically reviewed and approved the manuscript before submission.
Conflicts of Interest
Makoto Ishitobi has received speaker honoraria from Chugai, AstraZeneca, Pfizer, Taiho, and Kyowa Kirin outside the submitted work. Takahiro Nakayama has received speaker honoraria from AstraZeneca, Chugai, Novartis, Eli Lilly, Pfizer, Takeda, Daiichi-Sankyo, and Taiho outside the submitted work. Tadahiko Shien has received speaker honoraria from Daiichi-Sankyo, Eizai, Chugai, Kyowa Kirin, AstraZeneca, Pfizer, and Lilly outside the submitted work. Kanako Saito has received speaker honoraria from Daiichi-Sankyo, Chugai, Kyowa Kirin, Lilly, Novartis, Eizai, and Pfizer outside the submitted work. Kaori Terata has received speaker honoraria from AstraZeneca, Daiichi-Sankyo, Chugai, Lilly, Novartis, and Pfizer outside the submitted work. The remaining Authors have no conflicts of interest in relation to this study.
- Received January 14, 2023.
- Revision received January 21, 2023.
- Accepted January 23, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).