Optimizing Adjuvant Treatment Recommendations for Older Women with Biologically Favorable Breast Cancer: Short-Course Radiation or Long-Course Endocrine Therapy?

Round 1

Reviewer 1 Report

Dear authors, I am glad to read your latest submitted manuscript entitled “Optimizing adjuvant treatment recommendations for older women 2 with biologically favorable breast cancer: Short-course radiation or 3 long-course endocrine therapy?”

I suggest the following changes in order to improve the quality of the manuscript:

-please, clarify in the text what the authors mean with “lumpectomy” since it is not a specific term and there could be ambiguity across countries. In breast conserving therapy, lumpectomy is the excision of a breast quadrant (= quadrantectomy), while in other settings it could also mean nodulectomy.

-radiotherapy affects especially local recurrences, while endocrine therapy has a proven benefit on long-term outcomes such as OS. I would appreciate a more rigorous methodological discussion about these critical issues as they found the basic rationale for the existence of this review. In particular, I would put more emphasis on the survival gain obtained with endocrine treatment if weighted on the life expectancy of elder patients. This review should be a critical evaluation of the available literature based on the aforementioned biological rationale. On the contrary, it looks like a generic listing of clinical trial data.

Author Response

1. COMMENT 1: please, clarify in the text what the authors mean with “lumpectomy” since it is not a specific term and there could be ambiguity across countries. In breast conserving therapy, lumpectomy is the excision of a breast quadrant (= quadrantectomy), while in other settings it could also mean nodulectomy.

RESPONSE 1: Thank you for your this very important question and the opportunity to clarify. We agree that the term lumpectomy is ambiguous. Indeed, the 1.2022 version of the NCCN guidelines updated “lumpectomy” when used to “breast conserving surgery” given this ambiguity. Therefore, we have changed the use of “lumpectomy” to “breast conserving surgery” throughout the manuscript. Specifically, we have made this change on page 1 (lines 23 and 41), page 2 (lines 55, 57, 59, 64, and 98), page 4 (lines 187 and 195), page 5 (lines 201 and 233).

1. COMMENT 2: radiotherapy affects especially local recurrences, while endocrine therapy has a proven benefit on long-term outcomes such as OS. I would appreciate a more rigorous methodological discussion about these critical issues as they found the basic rationale for the existence of this review. In particular, I would put more emphasis on the survival gain obtained with endocrine treatment if weighted on the life expectancy of elder patients. This review should be a critical evaluation of the available literature based on the aforementioned biological rationale. On the contrary, it looks like a generic listing of clinical trial data.

RESPONSE 2: Thank you very much for your important comment and for the opportunity to improve the manuscript. We agree that there is an important tradeoff between the benefit of endocrine therapy (e.g., breast cancer specific mortality and survival) and risk of treatment particularly in elderly women with very low risk disease and/or limited life expectancy.  In this manuscript, we have sought to highlight pertinent clinical trial data that compare outcomes for women treated with endocrine versus radiation monotherapy. The randomized and retrospective data reviewed here demonstrate equivalent distant recurrence and overall survival for women treated with radiation monotherapy compared to endocrine monotherapy. We do not seek to argue that endocrine therapy should not be prescribed. Rather, we specifically have sought to review outcomes for older women with very low risk disease treated with radiation monotherapy and find that overall survival and distant relapse are not compromised when this approach is taken for appropriately selected patients. These data are reassuring, and pave the way for future research efforts designed to study radiation monotherapy as an alternative approach for those with low risk breast cancer who may be disinclined to take endocrine therapy.

            To illustrate these critical points, we have made the following changes to the manuscript: 

1. Page 1, 44 the sentence “Recently, there is growing interest in whether a short course of adjuvant radiotherapy may be more tolerable than 5 years of adjuvant endocrine therapy without compromising oncologic outcomes.” was adjusted to read “Recently, there is growing interest in whether a short course of adjuvant radiotherapy may be more tolerable than 5 years of adjuvant endocrine therapy without compromising oncologic outcomes, particularly among older women with low-risk disease.”
2. Page 4, line 133 the sentence “Given the toxicity associated with 5 years of endocrine therapy and reduced toxicity of radiotherapy in the modern era, it is important to consider whether a short course of radiotherapy alone may be preferable compared to 5 years of endocrine therapy for some older women with early stage, favorable-subtype breast cancer” was adjusted to “Given the toxicity associated with 5 years of endocrine therapy and reduced toxicity of radiotherapy in the modern era, it is important to consider whether a short course of radiotherapy alone may be an acceptable, alternative approach compared to 5 years of endocrine therapy for some older women with early stage, favorable-subtype breast cancer.”
3. Page 4 paragraph 2 was significantly adjusted to highlight these points:
   1. Old version: “Certainly, endocrine therapy is an important component of treatment for many women with HR-positive breast cancer. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of individual patient data from 20 trials showed that tamoxifen reduces local and distant recurrence, breast cancer specific mortality and contralateral breast cancer, although the absolute benefit depends on absolute breast cancer risks.^19,31–33 Aromatase inhibitors (AIs) are an alternative to tamoxifen for postmenopausal women, and randomized data has shown that treatment with AIs afford reduced recurrence rates and disease free survival compared to tamoxifen.^34–36”
   2. Adjusted version: “Certainly, endocrine therapy is an important component of treatment for many women with HR-positive breast cancer. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of individual patient data from 20 trials showed that tamoxifen impacts local and distant recurrence, breast cancer specific mortality, contralateral breast cancer, and overall survival. However, the absolute benefit of endocrine therapy depends on absolute breast cancer risk, such that patients with high-risk disease derive more benefit from endocrine therapy compared to those with low-risk disease.^19,31–33 Aromatase inhibitors (AIs) are an alternative to tamoxifen for postmenopausal women, and randomized data has shown that treatment with AIs afford reduced recurrence rates and disease free survival compared to tamoxifen.^34–36 However, in older women with comorbidities and/or limited life expectancy, benefit of adjuvant endocrine therapy must be weighed against risk of adverse events.”
4. Page 4, line 169: the following sentence was added “Indeed, current European Society of Breast Cancer Specialists/International Society of Geriatric Oncology guidelines for management of older women with breast cancer support omission of endocrine therapy among older women with very low-risk disease and/or short life expectancy in the absence of any documented effect on mortality in this population.⁴⁶”
5. Page 5, line 200 was adjusted from “While omission of endocrine therapy is less well-studied than omission of radiotherapy, select randomized studies have compared outcomes for women treated with adjuvant RT monotherapy versus ET monotherapy” to “While omission of endocrine therapy is less well-studied than omission of radiotherapy, a few randomized studies have demonstrated no difference in overall survival and distant recurrence among select women treated with adjuvant RT monotherapy versus ET monotherapy.^48–50”
6. Page 5, line 226 was adjusted from “Taken together, data from these older randomized studies indicate that there may be a group of women who can safely be treated with adjuvant RT monotherapy, with acceptable rates of distant recurrence and survival.” to “Taken together, data from these older randomized studies indicate that there may be a group of women who can safely be treated with adjuvant RT monotherapy, without compromising distant recurrence and survival.”
7. Page 6, line 254 was adjusted from “In a similar vein, modern population studies likewise reveal favorable outcomes for older women treated with adjuvant RT monotherapy.” to “In a similar vein, modern population studies likewise reveal favorable outcomes and no difference in overall survival for older women treated with adjuvant RT monotherapy compared to ET monotherapy.”
8. Page 7, line 309 was adjusted as follows from “Randomized and non-randomized data summarized here demonstrate favorable rates of local recurrence, distant relapse, and survival in this patient population with treated with radiation monotherapy.” to “Randomized and non-randomized data summarized here demonstrate favorable rates of local recurrence, distant relapse, and overall survival in this patient population with treated with radiation monotherapy.”

Reviewer 2 Report

Reviewer's report
Manuscript ID: Current Oncology 2063306
Title:  Optimizing adjuvant treatment recommendations for older women with biologically favorable breast cancer: Short-course radiation or  long-course endocrine therapy? 

Date:2022/12/5

Reviewer's report:
This is an interesting manuscript as it’s a comprehensive review aimed to investigate the feasiblity of omission of adjuvant endocrine therapy in favor of utilizing adjuvant radiotherapy alone to treat women with favorable early-stage breast cancer.  Endocrine therapy has proven benefit for women with hormone-sensitive breast cancers, and it has become standard-of-care following lumpectomy for those with hormone receptor (HR) positive  breast cancers. However, daily endocrine therapy for 5 years can be inconvenient as well,  is not without side effects, and many women have significant difficulty tolerating and/or  completing endocrine therap. This study thoroughly review the limitation of endocrine therapy. Final conclusion shows the favorable outcomeof post-op. adjuvant monotherapy with radiation therapy toward  local recurrence, distant mets or survival either randomized and non-randomized data .  I'm sure the result of this study could help physician as a clinical guidance for the management of older female with early  breast cancer  patient.

The MS is well prepared and containing a large amount of data.  Although, there remain some limitation . Nevertheless, it was still well written, thus, it should be published.

Author Response

Thank you for reviewing our manuscript and for your comments. We appreciate your summary and recommendation that it should be published.

Reviewer 3 Report

The paper entitled «  Optimizing adjuvant treatment recommendations for older women with biologically favorable breast cancer: Short-course radiation or long-course endocrine therapy? «  by Susan G. R. McDuff and Rachel C. Blitzblau is a review of the different works aiming to evaluate the benefit of adjuvant radiotherapy and/or hormonotherapy in older women with low risk breast cancer. The authors underline that whereas several studies focused on the possibility to omit breast adjuvant radiotherapy, omission of endocrine therapy among women receiving adjuvant radiation is less well-studied. However, available randomized and non-randomized data suggest that this approach may confer equivalent local control and survival whereas daily endocrine therapy for 5 years can be inconvenient for many women due to toxicity . Given improved convenience and lower toxicity associated with modern hypofractionated and partial breast radiotherapy approaches, some patients may prefer a radiation monotherapy approach. The authors underline the potential benefit of ongoing prospective tria that allow improved individualization of adjuvant therapy for future patients.

The paper is well written and the analysis of the relevant bibliography well conducted. This review is of interest for the readers.

Author Response

Thank you for reviewing our manuscript and for your thoughtful feedback. We appreciate your summary and time. We agree that this review may be of interest to Current Oncology readership