Adjuvant therapy for hormone receptor-positive breast cancer: Perspective from a survey on breast cancer physicians’ acceptance of practice-changing data

Abstract

A cross-sectional online survey was conducted. A high proportion of the Chinese breast cancer (BC) physician respondents (n=77) would prescribe extended adjuvant endocrine therapy (AET) with aromatase inhibitors (AI) beyond 5 years for postmenopausal females with BC, especially those with higher risk. Respondents with ≥15 years of clinical experience were more likely to prescribe a longer duration of AET for low-risk patients. Half of the respondents considered intermittent letrozole as an acceptable option. Most respondents would prescribe adjuvant chemotherapy to genomic high-intermediate risk [Oncotype DX recurrence score (RS) 21−25] females aged ≤50 years regardless of the clinical risk classification.

Adjuvant endocrine therapy (AET) prescription pattern of Chinese breast cancer (BC) physicians

Results from the Gruppo Italiano Mammella 4 (GIM4), the Secondary Adjuvant Long-Term Study with Arimidex (SALSA), and the Study of Letrozole Extension (SOLE) trials on extended AET or prescribing intermittent AET are practice-changing for the management of postmenopausal females with BC (1-3), but it was unknown whether physicians would accept these trial results and adjust their AET prescriptions for this patient group.

Likewise, the decision to prescribe adjuvant chemotherapy for hormone receptor (HR)-positive patients with intermediate Oncotype DX recurrence score (RS) risk remains controversial and there has been a lack of data to support such decisions (4). The Trial Assigning Individualized Options for Treatment (TAILORx) trial found that some patients with intermediate RS risk, especially those aged 50 years or younger, had some benefits by adding chemotherapy to their adjuvant AET regimens (5), and the Microarray In Node negative Disease may Avoid ChemoTherapy (MINDACT) trial suggested that high genetic risk is a more important factor as compared to high-risk clinical features (6). However, we suspected that some BC physicians may consider the absence of high-risk clinical features as an indication to safely forgo adjuvant chemotherapy for those with intermediate RS risk.

In an attempt to answer these questions, we conducted a cross-sectional online survey involving BC physicians in China in January 2022. The link to the online survey was sent to Chinese BC physician groups through a social media platform. A total of 77 BC physicians responded, and they were asked to indicate their medical specialties, the number of years of clinical experience, the location of practice, and the number of BC patients managed annually (personally or as a team). Ethics approval was not required for this study. This work was conducted in strict accordance with the human subject protection program.

The survey questions on extended or intermittent AET were developed based on the GIM4, SALSA, and SOLE trial results, as well as referred to the AET decision tree (section BINV-K) based on the latest National Comprehensive Cancer Network (NCCN) guidelines (1-3,7). This AET decision tree forms the basis of the survey questions pertaining to the duration of prior treatments [2−3 years of tamoxifen (TAM), 4.5−6.0 years of TAM, or 5 years of aromatase inhibitors (AI)]. The survey questions on prescribing adjuvant chemotherapy for patients with intermediate RS risk were developed based on the results of the TAILORx and MINDACT trials, as well as the fact that there remains a lack of guidance for this group of patients (4-6).

Statistical analyses were performed using SPSS Statistics (Version 28.0; IBM Corp., New York, USA). Non-parametric tests (Mann-Whitney U or Kruskal-Wallis, depending on the number of subgroups) were used to assess whether there was any difference in response between the subgroups.

Survey findings: What we learned

Most (62.3%) of the respondents were BC surgeons, 24.7% were BC specialists, 10.4% were medical oncologists, and 2.6% were general surgeons. The majority (71.4%) of respondents’ location of practice was in Tier 1 cities, followed by 10.4% in Tier 2 cities, 9.1% in Tier 3 cities, 2.6% in Tier 4 cities, and 6.5% in Tier 5 cities. Of note, this tier classification was based on the Chinese city tier system, with the most developed areas of the country being classified as Tier 1. Almost half (45.5%) of the respondents had a clinical experience of 15 years or more, whereas 54.5% had less than 15 years of clinical experience. The mean ± standard deviation (SD) number of BC patients managed annually was 762.10±1,254.50.

Prescribing extended AET for HR-positive, postmenopausal BC patients

Table 1 shows the survey results when respondents were asked about their usual practice when prescribing AET for HR-positive, postmenopausal BC patients considering the tumor characteristics and prior AET regimens. For patients with pN0, tumor size of 0.5 cm or smaller who had received either 4.5−6.0 years of TAM or 5 years of AI, the individual responses of those who chose to “add other duration of AI” (31.2% and 51.9%, respectively) indicated that most of them would stop the AET. Amongst the 35.1% of respondents who chose to “add other duration of AI” for patients with pN2/pN3 who had received 2−3 years of TAM, the individual responses indicated that they would add AI for up to 8−10 years.

Table 1. Respondents’ responses when asked about their usual practice when prescribing adjuvant AET for HR-positive, postmenopausal BC patients considering tumor characteristics and prior AET regimens.

Variables	%
	Add 2 years of AI	Add 5 years of AI	Add other duration of AI
AET, adjuvant endocrine therapy; HR, hormone receptor; BC, breast cancer; TAM, tamoxifen; AI, aromatase inhibitors.
pN0, tumor size ≤0.5 cm, received 2.0−3.0 years TAM	40.3	55.8	3.9
pN0, tumor size ≤0.5 cm, received 4.5−6.0 years TAM	46.8	22.1	31.2
pN0, tumor size ≤0.5 cm, received 5.0 years AI	32.5	15.6	51.9
pN1mi or pN1, tumor size >0.5 cm, received 2.0−3.0 years TAM	2.6	84.4	13.0
pN1mi or pN1, tumor size >0.5 cm, received 4.5−6.0 years TAM	22.1	76.6	1.3
pN1mi or pN1, tumor size >0.5 cm, received 5.0 years AI	27.3	63.6	9.1
pN2 or pN3, received 2.0−3.0 years TAM	0	64.9	35.1
pN2 or pN3, received 4.5−6.0 years TAM	6.5	90.9	2.6
pN2 or pN3, received 5.0 years AI	7.8	88.3	3.9

For patients with pN0 and tumor size of 0.5 cm or smaller, respondents with 15 years or more of clinical experience were more likely to prescribe a longer duration of AET as compared to those with less than 15 years of clinical experience (P=0.025 for patients who had received prior 4.5−6.0 years of TAM and P=0.038 for those who had received prior 5 years of AI).

Prescribing intermittent AET for HR-positive, postmenopausal BC patients

More than half (57.1%) did not agree with the hypothesis that AI resistance can be reversed by intermittent letrozole treatment (the SOLE trial hypothesis), but 50.6% considered intermittent letrozole as an acceptable option for patients who would prefer a treatment interruption, especially for those with 3 or less positive nodes (79.5%), tumor grade 1 (84.6%), tumor size of 2 cm or smaller (82.1%), and human epidermal growth factor receptor 2 (HER2)-negative disease (74.4%). Two-thirds (66.7%) of the respondents did not consider intermittent AET as acceptable for patients who had only received selective estrogen receptor modulators (SERMs).

The respondents’ responses were almost divided when considering other factors such as whether the patient had received prior chemotherapy (59% of respondents voted that intermittent AET is acceptable), underwent mastectomy (59% voted yes), and received radiotherapy (43.6% voted yes).

Prescribing adjuvant chemotherapy for node-negative, HR-positive BC patients with intermediate RS risk

For patients aged 50 years or younger with RS of 16−25, almost all (97.4%) of the respondents would prescribe adjuvant chemotherapy. However, for patients aged older than 50 years with RS of 16−25, two-thirds (68.8%) of the respondents would not prescribe adjuvant chemotherapy.

For patients aged 50 years or younger with high-intermediate RS (defined as RS of 21−25) and high-risk clinical features, almost all (98.7%) of the respondents would prescribe adjuvant chemotherapy. For patients aged 50 years or younger with high-intermediate RS, but without high-risk clinical features, the majority (87.0%) of the respondents would still prescribe adjuvant chemotherapy.

Key takeaways: Analyzing survey results and uncovering three critical findings

The results of this survey show several important findings (Table 2). Firstly, a high proportion of the BC physician respondents would prescribe extended AET with AI beyond 5 years for postmenopausal females with BC, especially for those with higher risk. Secondly, intermittent letrozole was considered as an acceptable option for low-risk patients. Thirdly, forgoing adjuvant chemotherapy in younger females with genomic high-intermediate risk (RS of 21−25), but clinical low risk was not considered as acceptable by the BC physician respondents.

Table 2. Key takeaway messages from the survey.

No.	Key takeaway messages
BC, breast cancer; AET, adjuvant endocrine therapy; AI, aromatase inhibitor.
1	A high proportion of BC physician respondents would prescribe extended AET with AI beyond 5 years for postmenopausal females with BC.
2	For low-risk patients, 5 years of AET is acceptable, but a more experienced physician tends to take a more conservative approach and prescribes a longer duration of AET.
3	For intermediate- to high-risk patients, the optimal duration is unknown but 7−8 years of AET appears to be the “sweet spot”.
4	For high-risk patients, at least 10 years of AET may be warranted.
5	Intermittent letrozole can be considered for low-risk patients, especially for those with potentially poor adherence to extended AET.
6	Adjuvant chemotherapy should be prescribed to genomic high-intermediate risk females aged 50 years or younger regardless of the clinical risk classification.

A large meta-analysis involving 88 trials and 62,923 patients has previously found that the risk of BC recurrence persisted beyond the first 5 years of AET and continued to occur steadily for at least 20 years after the diagnosis (8). In an attempt to find the optimal duration of AET, so as to not overtreat and cause an increased incidence of side effects from the treatment, the findings from the GIM4 and SALSA trials can be collectively interpreted to suggest that a total of 7−8 years may be the optimal extended AET duration for BC patients with average risk (1,2).

BC physician respondents in the present study seemed to agree with the results of these trials and would prescribe extended AET with AI beyond 5 years for high-risk postmenopausal females with BC. Nonetheless, it is apparent from the survey results that some BC physicians remain conservative in terms of prescribing AET to low-risk patients (defined as pN0, tumor size of ≤0.5 cm in this survey), with 22.1% choosing to add 5 years of AI to patients who had already received 4.5−6.0 years of TAM, as well as 15.6% choosing to add 5 years of AI to patients who had already received 5 years of AI. Since the more experienced BC physicians (i.e., those with more than 15 years of clinical experience) were found to be more likely to prescribe a longer duration of AET for low-risk patients in subsequent analysis, and these findings may suggest that a more conservative approach in terms of AET prescriptions is preferred by BC physicians with more clinical experience. Considering that clinicopathologic features may not reliably predict who will benefit from extended AET, the use and validation of the Breast Cancer Index, which integrates the HOXB13:IL17BR (H/I) gene expression ratio and molecular grade index (MGI) components (9), are warranted for extended AET use in low-risk patients (10).

Multigene panel testing could also be used to guide extended AET decisions on patients with intermediate- to high-risk, as the BC physician respondents in this study were not comfortable with prescribing just 5 years of AET for this group of patients. Although 7−8 years of AET appears to be the “sweet spot” based on the results of GIM4 and SALSA, the optimal duration (i.e., choosing between 5−10 years) remains unknown and therefore this decision should be personalized and discussed thoroughly with the patient. The addition of adjuvant S-1 for 1 year or abemaciclib for 2 years should also be considered based on the clinical benefits shown in the POTENT (adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial) and monarchE (Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early BC) trials, respectively (11,12).

The SOLE study was initially designed to assess whether the recovery of circulating estrogen levels through intermittent AET with letrozole would result in an improved disease-free survival (DFS), but the results showed no improvement in DFS as compared to those who received continuous letrozole [7-year DFS of 81.4% in the intermittent group vs. 81.5% in the continuous group; hazard ratio: 1.03, 95% confidence interval (95% CI): 0.91−1.17] (3). Nonetheless, the less worsening in symptom-specific and global quality of life in those who received intermittent AET is an interesting finding which suggests that intermittent letrozole could be a viable option for patients who would require or prefer to do so (3). The respondents of the present study seemed to agree that intermittent letrozole is an acceptable option for low-risk patients, and this may represent an important strategy to combat patients’ potentially poor adherence to extended AET.

Lastly, seeing that the MINDACT trial found excellent survival in patients with genomic low risk and clinical high risk who forgo adjuvant chemotherapy, it appears that genomic risk plays a more important role in the decision to safely omit adjuvant chemotherapy in younger females (6). The respondents of the present survey seemed to agree with this consideration as well as the results of the TAILORx trial (5), and the vast majority of the BC physicians would prescribe adjuvant chemotherapy to genomic high-intermediate risk females aged 50 years or younger regardless of the clinical risk classification. This is understandable due to the fact that there is an enhanced chemotherapy effect in younger females with BC, which was three times larger in younger females than in older females, potentially due to chemotherapy-induced ovarian function suppression (6,13). However, it should be noted that it remains unknown whether an ovarian function suppression may replace chemotherapy and produce the same benefits (6,14).

To the best of our knowledge, this survey was the first to explore the BC physicians’ acceptance on the aforementioned novel, practice-changing data for the management of patients with HR-positive BC. Although the interpretations could be limited due to the nature of the survey, the findings provide insight into the real-world prescription pattern of BC physicians and their acceptance of new data.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Working group members

AICO Expert Panel (listed alphabetically in order of surname; full list is available on https://www.aiconcology.org/):

Fan Chai　The First Affiliated Hospital, Army Medical University

Yiding Chen　The Second Affiliated Hospital, Zhejiang University

Louis Wing-Cheong Chow　Organization for Oncology and Translational Research

Xiaoxing Duan　Huashan Hopital Affiliated to Fudan University

Peifen Fu　The First Affiliated Hospital, Zhejiang University

Wenjing Jian　Shenzhen Second People’s Hospital

Wen Kang　Xiyuan Hospital of China Academy of Chinese Medical Sciences

Rui Ling　Xijing Hospital, Air Force Medical University

Hongguang Liu　Shenzhen Second People’s Hospital

Simin Luo　Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Hongmin Ma　Guangzhou Women and Children’s Medical Center

Ke Qi　Nanshan District People’s Hospital

Die Sang　Sanhuan Cancer Hospital

Li Su　People’s Hospital of Ningxia Hui Autonomous Region

Zihan Sun　Guiqian International General Hospital

Cheng Wang　The Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Nan Wang　Peking University Cancer Hospital and Institute

Ruliang Wang　Hehai University

Wei Wang　Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Ying Wang　Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Wei Wei　Peking University Shenzhen Hospital

Yu Xiao　Shenzhen Second People’s Hospital

Jiandong Ye　Suzhou Ninth Hospital Affiliated to Soochow University

Yinduo Zeng　Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Chao Zhang　Affiliated Hospital of Jiujiang University

Yi Zhang　The First Affiliated Hospital, Army Medical University

Wenbin Zhou　The First Affiliated Hospital, Nanjing Medical University

Li Zhu　Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine