Letters to the Editor

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In a Subset of de Novo Stage IV Patients, There Will Be a Survival Benefit: Listen to the Other Side of the Story

We read the article, titled “To Operate or Not in De Novo Stage IV Breast Cancer: Is That Still a Question?” by Preeti D. Subhedar, MS, MD, FACS, Sarah Blair, MD, FACS, and Judy C. Boughey, MD, FACS, published in the June 2022 issue of the ACS Bulletin, and we’d like to express our thoughts on this subject. We think that their comments and conclusions seem biased and reductive, particularly for a topic complicated by widely disparate presentations of the extent of metastatic disease, phenotypes, and responsiveness to metastatic therapy.

The paradigms of breast cancer treatment have drastically evolved from standard care to individualized treatment. Therefore, it is crucial to assess the patient by considering his or her age, the clinical and pathological characteristics of the tumor, the organ where the metastasis is located, and the extent of the metastasis in de novo stage IV breast cancer (BC).

We believe that the question is not whether primary surgery is beneficial in de novo stage IV BC, but who is a good candidate for it (see Figure 1). A patient who may have overall (OS) and loco-regional progression free (LRP) survival benefits from loco-regional treatment (LRT) include:

• Patients who receive systemic therapy for a while and images revealed that no evidence of distant metastasis
• Systemic therapy (ST) controls distant metastasis (no progression or regression)
• Progression of the primary breast tumor
• Solitary (oligo) distant organ metastasis such as bone, liver, and lung
• Patients who underwent an intervention for oligo/solitary metastasis followed ST and no new metastasis
• Patients with only sternum metastasis

Evidence of survival benefits include:

• Study shows the OS rates of 98% (95% CI: 94.6%–100%) at both 5 and 10 years in patients with human epidermal growth factor receptor (HER2) (+) de novo stage IV BC when they reach no evidence of disease (NED). The progression-free survival was 100% at 5 and 10 years, indicating no progression events for any of the patients. A strategy involving ST and resecting or radiating residual disease and continuing maintenance therapy with an HER2-targeted agent and endocrine therapy, if appropriate, is recommended.¹
• The long-term results of the MF 07-01 study² showed that local control provides a significant survival advantage in all subgroups except for the patients with triple-negative BC in both 5-year and 10-year OS (5-year OS: 42% for LRT vs. 24% for ST, HR: 0.66, p = 0.005 and 10-year OS: 19% for LRT vs. 5% for ST, HR: 0.71, p = 0.0003). Hazard of death decreased 29% in the primary surgery group in 10 years. The BOMET study, which is a prospective multicenter registry study, compared ST-only with LRT with ST and showed that receiving adjuvant locoregional treatment for bone-only metastasis stage IV breast cancer reduces the risk of death 60% in 3 years follow-up.
• The BOMET study³ showed that 5-year OS was 75%, 72%, and 69% in patients who underwent LRT with solitary metastasis, oligometastases, and multiple metastases, respectively, but these rates were 45%, 42%, and 31%, respectively, in the ST group (p<0.05). 5-year OS rates were 76% in solitary and 70% in oligometastatic patients in the ST+LRT group, while it was 74% and 76% in the LRT+ST group, respectively. There was no OS benefit for starting with ST in solitary and oligometastatic disease. However, the study showed a statistically significant difference in the 5-year OS rate in patients with multiple bone metastasis, especially with more than five metastases; these were 83% and 67% in the ST+LRT group, respectively. In contrast, 5-year OS rates were 55% for those with multiple metastases and 31% in patients with more than five bone metastases in the LRT+ST group. Starting with ST followed by LRT in patients with a higher metastatic disease burden seems to be a more rational approach.
• Several meta-analyses, prospective observational studies, and retrospective studies showed similar result as approximately 30%–40% reduction in death with LRT compared with ST only.
• All randomized clinical trials and retrospective studies on this topic showed the benefit of LRP-free survival interval with primary breast surgery in this cohort of patients; E2108 trial⁴ LRP is 39.8% in the ST-only group and 16.3% in the LRT group. In MF07-01 Study LRP is 1% in the LRT group and 14% in the ST group. In the Indian Study⁵ LRT resulted in a significant improvement in LRP-free survival compared with that in the ST-only group (median not attained vs. 18.2 months [95% CI 15.1–21.3]; HR 0.16, 95% CI 0.10–0.26; p<0.0001).
• The MF07-01Q study demonstrates that patients who had LRT had similar physical and mental health outcomes compared with those who had ST only in a cohort of patients who lived longer than 3 years, and de novo stage IV BC patients had mental health scores comparable to those with early stage BC.⁶

Attendees at one of the world’s most prestigious meetings, the St. Gallen International Breast Cancer Consensus Conference in 2021, stated that the panel continues to endorse first-time curative intention for oligometastatic BC, for example, with isolated metastasis in the sternum (85%), isolated metastasis to bone, or single nodule (82%). Some were even following curative intent after multiple metastases had responded well to primary ST (29%).⁷

We believe that concluding that LRT has no place in de novo stage IV BC treatment eliminates the possibility of long-term NED or even a cure. LRT as a treatment option for intact primary tumor for de novo stage IV BC needs to be considered case-by-case (individualize treatment) with input and discussion from all stakeholders. The fact that many patients, most of whom are oligometastatic (low tumor burden), have been shown to benefit more from ST and/or LRT in many studies and in daily practice, perhaps, necessitates a new staging system where these patients would be included in a group other than stage IV. Surgeons should be aware that the subset of de novo stage IV BC patients have a survival benefit from LRT, and that timing the intervention allows us to take advantage of the window of time before the disease progresses.

In conclusion, the goal should be to identify any subset of de novo stage IV patients that might potentially benefit in terms of OS, recognize who they are, and when definitive LRT should be delivered rather than issuing a blanket statement to all surgeons in the American College of Surgeons that they are obligated to tell every patient considering local treatment that there is no survival benefit.

Atilla Soran, MD, MPH, FNCBC, FACS, Serdar Ozbas, MD, FEBS, Vahit Ozmen MD, FACS
On behalf of Breast Health Working Group International

References

1. Wong Y, Raghavendra AS, Hatzis C, et al. Long-term survival of de novo stage IV human epidermal growth receptor 2 (HER2) positive breast cancers treated with HER2-targeted therapy oncologist. Oncologist. 2019;24(3):313-318.
2. Soran A, Ozmen V, Ozbas S, et al. Primary surgery with systemic therapy in patients with de novo stage IV breast cancer: 10-year follow-up; Protocol MF07-01 randomized clinical trial. J Am Coll Surg. 2021;233(6):742-751.
3. Soran A, Dogan L, Isik A, et al. The effect of primary surgery in patients with de novo stage iv breast cancer with bone metastasis only (Protocol BOMET MF 14-01): A multi-center, prospective registry study. Ann Surg Oncol. 2021;28(9):5048-5057.
4. Khan SA, Zhao F, Goldstein LJ, et al. Early local therapy for the primary site in de novo stage IV breast cancer: Results of a randomized clinical trial (EA2108). J Clin Oncol. 2022;40(9):978-987.
5. Badwe R, Hawaldar R, Nair N, et al. Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: An open-label randomised controlled trial. Lancet Oncol. 2015; 16(13):1380-1388.
6. Soran A, Soyder A, Ozbas S, et al. The role of loco-regional treatment in long-term quality of life in de novo stage IV breast cancer patients: Protocol MF07-01Q. Support Care Cancer. 2021;29(7):3823-3830.
7. Thomssen C, Balic M, Harbeck N, Gnant M. St. Gallen/Vienna 2021. A brief summary of the consensus discussion on customizing therapies for women with early breast cancer. Breast Care (Basel). 2021;16(2):135-143.