Survival outcomes and tumor response to primary endocrine therapy in the non-operative management of early breast cancer: a retrospective observational study

Introduction

There are limited guidelines for the non-operative management of patients with hormone responsive early breast cancer (HR⁺ EBC), often patients within this group are underrepresented in practice changing clinical trials due to their age, comorbidities, and functional status (1,2). Due to the lack of high-level evidence, oncologists are therefore in the challenging position of making treatment decisions for a heterogenous group of patients where performance status, comorbidities and patient preference must be considered in a comprehensive assessment against the benefits of conventional radical treatment options (2,3).

For patients with EBC, current guidelines recommend upfront surgery followed by adjuvant therapies. Primary endocrine therapy (PET) is reserved for patients who are unfit for or decline surgery (4). Evidence from a Cochrane review by Hind et al. looking at elderly patients, showed no overall survival (OS) difference between surgery with or without adjuvant tamoxifen versus tamoxifen alone (5). This Cochrane review undertook meta-analysis of seven randomised controlled trials (RCTs) looking at women over 70 years old (5), of note there did appear to be inferior locoregional disease control for patients on PET (5,6). A systematic review of six RCTs and 31 non-randomised studies highlighted a survival and disease control advantage of surgery over PET in patients with a life expectancy of more than 5 years (6,7), from this we can infer that surgery should be recommended for those with longer life expectancy.

Long term analysis of a randomised (EPSII) trial in Nottingham looking at 147 oestrogen receptor (ER) rich (H score >100), node negative patients showed no significant difference in local or distant recurrence or OS between surgery vs. tamoxifen (8), hence suggesting in ER rich patients PET has the potential to deliver equal outcomes to surgery.

Our objective in conducting this study was to evaluate the survival outcomes and tumor responses of patients with HR⁺ EBC treated with PET, thereby providing real world evidence that might better inform clinical practice in this challenging arena. We present this article in accordance with the STROBE reporting checklist (available at https://abs.amegroups.com/article/view/10.21037/abs-24-10/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the regional ethics board of Frimley Health NHS Foundation Trust, Quality and Audit team (No. CB094) and individual consent for this retrospective analysis was waived.

This retrospective observational single institution study was conducted to identify the survival and tumour response outcomes for patients with HR⁺ EBC treated with physician’s choice PET in a specialist breast oncology clinic based in Berkshire from 2004 to 2021. Patients were included in the study if they were unfit for treatment or had declined radical treatment options. Patients were excluded from the study if they had surgery, chemotherapy, or radiotherapy to the breast of greater intensity than single 8 Gy. All patients in this clinic were required to comply with PET and undergo regular clinical and ultrasound review.

Patient letters were reviewed to determine rationale for choice of treatment and change of treatment. Histological reports were reviewed to determine tumour size at diagnosis (in millimetres), laterality, tumour type, grade, HR status and HER2 status. Progression-free survival (PFS) through first-line PET was measured from the date of commencement of PET to clinical or radiological progression. PFS through second-line PET was measured from the date of commencement of second-line PET to clinical or radiological progression. OS was measured from date of diagnosis to progression, death or conclusion of the study observation period. This data was presented graphically on a Kaplan-Meier survival curve. Three to six monthly ultrasound reports were retrospectively reviewed to determine response to treatment against RECIST 1.1. criteria (9). The time to best response was measured from date of commencement of first-line PET to date of best response as measured by ultrasound.

Results

Patient characteristics

One hundred and forty-eight patients treated at the Berkshire oncology clinic were identified as potentially eligible and of these 61 patients met the inclusion and exclusion criteria. The flowchart in Figure 1 depicts patient selection in more detail.

Figure 1 Flowchart of participant selection process. PET, primary endocrine therapy.

They had a median age of 82 years (range, 27–97 years) and were retrospectively reviewed over a median period of 7 years (range, 2–13 years). Retrospective review of patient letters confirmed radical treatment options were inappropriate in this patient group due to poor performance status, comorbidities, inability to comply with treatment and patient choice.

With reference to Table 1, most tumours had lower-risk features at presentation; 82% ER and progesterone receptor (PR) positive, 66% HER2 negative, 87% unifocal, 85% T1 or T2, 82% grade 1 or 2 and 66% with no nodal involvement. Invasive ductal cancer was the most common histological type observed (62%), with lobular cancer being the second most common (20%).

Response to treatment

Patients were commenced on physicians’ choice of PET with 79% prescribed letrozole first line, 71% prescribed exemestane second line and 46% prescribed tamoxifen third line. A switch to a different endocrine was indicated by progressive disease or difficulty tolerating treatment due to side effects. During the period of follow-up; 57% of patients remained on first-line PET, 30% were switched due to progressive disease and 13% were switched due to intolerable side effects.

Median PFS through first-line PET was 57 months (range, 8–115 months) and median PFS through second-line PET was 22 months (range, 2–61 months). The Kaplan-Meier curve for patients on first-line PET is displayed in Figure 2; 5-year OS based on this is 63% and the 10-year OS is 24%. Twenty-five patients were censored where the total survival time could not be determined; for example, where there was loss to follow-up or the end of study was reached with no available data thereafter. End of study reached and no available data thereafter.

Figure 2 Kaplan-Meier survival curve for patients on primary endocrine therapy.

Tumour size measurements using 3–6-month serial ultrasound were collected comprehensively in 89% of patients on first-line PET and 100% patients on second-line PET. The median time to best response on first-line PET was 25 months (range, 4–112 months), the median percentage change in longest diameter tumour size at the point of best response was a decrease in size of 60% (range, 3.3% to 100%). On first-line PET, 34% of patients had complete response, 29% had partial response, 25% had stable disease and 13% had progressive disease referencing RECIST 1.1. criteria (9). The waterfall plot in Figure 3 depicts these results diagrammatically. Looking at complete responders more closely in the first-line setting, all patients had strongly positive Allred score of 8 for the ER and variable PR scores between PR5 to PR8. Forty-seven percent had ER8 PR8 positivity.

Figure 3 Percentage change in tumour size from diagnosis on first-line endocrine therapy.

Discussion

We retrospectively reviewed 61 women with HR⁺ EBC treated with PET, who would have otherwise been unsuitable or unfit for more intensive radical treatment options. Time to best response was 25 months and at the point of best response, there was a 60% median reduction from the original tumour size as measured by serial ultrasound evaluation. Remarkably we demonstrated that with non-operative management, these women had a 63% 5-year OS, 24% 10-year OS and 63% objective response rate (ORR) on first-line PET. Where patients are not fit for radical treatment, PET may be employed as the mainstay of treatment with the added benefit of fewer hospital visits and reasonably tolerable side effects (2,3). Notably for our patients, only 13% were switched to a different PET citing intolerable side effects and 30% due to progressive disease.

Looking more closely at the 34% of patients who had complete response, there was a pattern of strong HR positivity. This suggests that strong HR positivity correlates with clinical benefit, mirroring the results of a large study by Syed et al. [2011] looking at 1,065 ER positive over 70 year olds with EBC, which also showed clinical benefit in 97.9% of patients within the first 6 months of PET use and a median time to progression of 49 months (10).

Interestingly studies looking at patients with strongly HR⁺ EBC not only show higher rates of clinical benefit but also no significant differences in local, distant recurrence or OS between surgery and PET (6,8,10). Of the two Nottingham trials looking at PET vs. surgery, EPSI had patients who were unselected for ER status and EPSII had patients with strong ER positivity. It was shown ORR on PET went from 59% (EPSI) to 79% (EPSII), these rates are in line with the 63% ORR observed in our study (6,8). The clinical benefit in the strongly ER positive group may be underestimated. Further evaluation of tumour biology beyond ER expression may be required (6).

Our cohort included one 27-year-old who opted for non-operative management; however overall, the cohort was of an older age group with median age 82 years (range, 27–97 years). Biologically, the literature suggests that tumours in the older population are less aggressive and have indolent features such as lower grade, less axillary node involvement, less vascular invasion, higher ER/PR positivity and HER2 negativity (2,3,11-13). Older patients are under-represented in many practice-changing clinical trials and factors other than survival (quality of life, performance status and life expectancy) are more meaningful in guiding decision making in this population (10). It is important to highlight that the presence of comorbidities itself is associated with increased mortality and decreased OS as shown in a study of 64,034 older breast cancer patients in which 13 comorbid conditions were examined (14-16).

Considering the median age of 82 years, we noted prescribing preferences leaned more towards aromatase inhibitors (AIs). For post-menopausal women, AIs are the preferred choice, as the aromatase enzyme is predominantly responsible for peripheral conversion of testosterone and androstenedione to oestrogens (3). Several phase III adjuvant trials and one RCT comparing surgery vs. PET were referenced to evaluate efficacy of AIs (letrozole, anastrozole and exemestane) over tamoxifen in guiding choice of PET (1,3,7,14,15,17-23). Additionally, there is retrospective evidence from the Nottingham cohort that patients had a longer median time to progression with AI compared to tamoxifen (60 vs. 48 months; P=0.02) (6).

Through review of clinic letters, we noted that physicians practicing in this clinic were commonly faced with compliance issues, side effects, polypharmacy and social factors that impact treatment in all breast oncology clinics (1,10,15). This data reflects real-world survival outcomes and measurements of tumour response achievable on PET in a group of patients who are often excluded from larger practice changing studies.

Particularly for older or comorbid patients, the issue of under or overtreatment is challenging to establish. This might be better addressed with multidisciplinary collaboration between geriatricians and oncologists as well as objective tools such as the comprehensive geriatric assessment (6,14-16,20,21). However, these measures are challenging to implement due to time constraints in clinic and the scarcity of geriatric speciality presence in breast oncology multidisciplinary meetings.

This study is indeed limited in that it is retrospective, non-randomised, single armed, single centre and observational in nature. Additionally, this study is not highly controlled or adjusted for confounders such as age, comorbid conditions or receptor status which are likely to affect survival and tumour response. Caution is required when interpreting the results as they may not be generalizable. However, given the paucity of high-level evidence in this arena and that 42% of over 70 year olds in the United Kingdom are treated primarily with PET (6,20), the results of this study are valuable and applicable to patients who are not being radically treated for their breast cancer and therefore require an individualised approach.

Conclusions

The non-operative management of breast cancer in older women is a complex and challenging arena. The results of this study add to the evidence base in favour of recommending PET as a reasonable alternative option for HR⁺ EBC, where performance status, life expectancy, quality of life and patient choice must be weighed holistically against the benefits of radical treatment options (2,21). Particularly for those patients with strong HR positivity, there is evidence to suggest excellent clinical and survival outcomes where patients are treated with PET.

Acknowledgments

This study was presented as a poster presentation at the UK Breast Cancer Group Conference which took place in London during November 2022. The condensed form of the abstract was subsequently published in June 2023 in the Journal of Clinical Oncology, volume 35, issue 6.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://abs.amegroups.com/article/view/10.21037/abs-24-10/rc

Data Sharing Statement: Available at https://abs.amegroups.com/article/view/10.21037/abs-24-10/dss

Peer Review File: Available at https://abs.amegroups.com/article/view/10.21037/abs-24-10/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://abs.amegroups.com/article/view/10.21037/abs-24-10/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the regional ethics board of Frimley Health NHS Foundation Trust, Quality and Audit team (No. CB094) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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