Ann Surg Oncol

https://doi.org/10.1245/s10434-018-6664-6

EDITORIAL – BREAST ONCOLOGY

De Novo Stage 4 Metastatic Breast Cancer: A Surgical Disease?

Brigham and Women’s Hospital, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA

The diagnosis for 6% of new breast cancer cases each surgical group, mainly through matched pair analysis, show
year in the United States is de novo metastatic disease or this survival benefit to be no longer apparent,6–8 high-
stage 4 at presentation. Although treatment for these lighting the need for randomized prospective trials.
patients is largely centered around systemic therapy, with In December of 2013, two prospective randomized trials
local therapy (surgery and/or radiation therapy) largely led by Soran et al.9 (Turkey) and Badwe et al.10 (India)
reserved for palliation, it has been postulated that resection were introduced through oral presentations at the San
of the primary breast cancer may improve survival. This Antonio Breast Cancer Symposium. The prospective trial
controversy is illustrated by the National Comprehensive by the Tata Memorial Center conducted by Badwe et al.,10
Cancer Network (NCCN) guideline, which states, ‘‘the role which evaluated the effect that removal of the primary
and timing of surgical removal of the primary (breast tumor and axillary lymph nodes has on OS and progres-
cancer) in patients presenting with de novo stage IV dis- sion-free survival, was subsequently published in 2015.11
ease is the subject of ongoing investigations.’’ The study randomized 350 patients between 2005 and 2013
The rationale for proceeding with surgical intervention based on site of distant metastases, number of metastatic
includes the possibility of increasing immunomodulation lesions, and hormone receptor status. The patients with a
and chemotherapy effectiveness through decreased tumor resectable primary breast cancer that could be treated with
burden, decreasing metastatic potential by eliminating endocrine therapy were assigned up front, whereas those
breast cancer stem cells, disrupting the seeding potential of with unresectable metastatic disease were treated with
new metastases, and decreasing the likelihood of resistant chemotherapy before randomization (which was then based
disease. On the other hand, it has been argued that surgical on objective tumor response to chemotherapy). Notably,
intervention may result in delayed administration of sys- the patients with human epidermal growth factor 2
temic therapy, surgical morbidities, loss of the primary (HER2)-positive disease were not treated with HER2-di-
cancer as a marker of disease response, and disruption of rected therapy, which would not be considered standard of
cytokines that may restrict the growth of distant metastases. care in most developed countries. Badwe et al.10 reported
A review of retrospective studies on the management of that locoregional resection of the primary tumor did not
de novo metastatic breast cancer has largely shown mixed increase OS for the patients who had responded to front-
findings, with some studies reporting an improved overall line chemotherapy.
survival (OS) of 1–2 years with surgical intervention.1–5 Unlike the findings of the Tata Memorial Center, Soran
However, the patients in the surgical group often were et al., in this current issue of Annals of Surgical Oncology,
younger and had less metastatic disease burden. Other present the first randomized study to show a statistically
retrospective studies accounting for selection bias in the significant improvement in median survival with surgery
for patients with de novo stage 4 breast cancer at the 5-year
follow-up assessment.9
In this multicenter, phase 3, randomized control trial
(MF07-01), conducted in Turkey, which compared
Ó Society of Surgical Oncology 2018 locoregional treatment (LRT) or surgery followed by sys-
First Received: 9 July 2018 temic therapy (ST) versus ST alone for naı̈ve stage 4 breast
cancer patients, Soran et al.9 reported a reduction in the
M. Golshan, MD hazard of death for 34% of the former group at 40 months
e-mail: mgolshan@bwh.harvard.edu
 T. U. Barbie, M. Golshan

(hazard ratio [HR], 0.66; 95% confidence interval [CI], used a nonstandard statistical justification, which they
0.49–0.88; p = 0.0050). This reduced hazard of death was argued was based on treatment-effectiveness analysis
not evident in a shorter follow-up period of 36 months with adjusted for covariates by use of multivariate analysis after
a median follow-up period of 54.5 months. Interestingly, stratification. It is also important to note that the LRT
by the fifth year of follow-up evaluation, 41.6% (95% CI, group had higher rates of ER/PR-positive disease (85.5%
32.5–50.4) of the patients were alive in the LRT group vs. 71.8%; p \ 0.05) and lower rates of triple-negative
versus 24.4% (95% CI, 16.9–32.6) in the ST group disease (7.3% vs. 17.4%; p \ 0.05). Therefore, the patients
(p = 0.005). This study included 274 patients, and most of in the LRT group most likely had less aggressive disease. It
the LRT patients (102/138, 74%) underwent a mastectomy also was discussed that among patients with triple-negative
and axillary lymph node dissection, with ST started breast cancers, the median survival was 17.5 months in the
approximately 27.1 ± 9.9 days after surgery. The ST reg- LRT group and 18 months in the ST group (HR, 0.74; 95%
imens, including chemotherapy and bisphosphonates, were CI, 0.32–1.75; p = 0.49). Given that the ST group had
similar between the two groups (p [ 0.05). In the LRT more patients with triple-negative breast cancer, this likely
group, 38% of the patients received post-mastectomy also contributed to the reported difference in survival
radiation therapy (PMRT), and the median survival did not outcomes. In addition, when the 3-year survival of the
differ between the patients with PMRT and those without patients with multiple pulmonary/liver metastases was
PMRT (p = 0.36). In addition, the rates of irradiation and analyzed, the LRT group showed a markedly lower sur-
surgical intervention to metastatic sites were similar vival (31%; 95% CI, 9–55%) than the ST group (67%; 95%
between the two groups (p = 0.07). CI, 38–85%) (p = 0.05). Furthermore, solitary bone
Although the study’s primary aim was to assess LRT metastasis was not confirmed by biopsy, but instead, the
efficacy in relation to OS, unplanned subgroup analyses diagnosis was based on two imaging methods, namely,
showed OS to be longer for the LRT group with respect to whole-body scintigraphy and FDG-PET/CT. Finally, it is
estrogen receptor (ER)/progesterone receptor (PR) plus difficult to discern whether the issue of lead time bias was
disease (HR, 0.63; 95% CI, 0.44–0.89; p = 0.008), HER2/ addressed by Soran et al.9 Some patients in the trial likely
neu(–) (HR, 0.64; 95% CI, 0.45–0.91; p = 0.01), age had a shorter time from metastatic diagnosis to treatment,
younger than 55 years (HR, 0.57; 95% CI, 0.38–0.86; whereas other patients may have had metastatic disease for
p = 0.007), and solitary bone-only metastasis (HR, 0.47; a longer period.
95% CI, 0.23–0.98; p = 0.04). These findings are similar to The MF07-01 study findings have important implica-
those reported in prior meta-analyses, such as the studies tions by further emphasizing the complexity and
by Harris et al.12 and Petrelli and Barni.13 Another sec- heterogeneity of breast cancer biology. Like prior studies,
ondary end point investigated by Soran et al.9 was the rate the findings of Soran et al.9 continue to show that patients
of locoregional progression/recurrence, defined as clini- with de novo stage 4 metastatic breast cancer who present
cally or radiographically documented size progression of with triple-negative disease and/or pulmonary or liver
the primary tumor, ulceration, bleeding, fungation, or metastases will not benefit from LRT. Patients who did
findings of new locoregional lesions. The authors state that benefit from LRT were younger women who mainly had
the rate was 11 times higher in the ST group. Another ER?/PR?/HER2/neu(–) disease. It is difficult, however, to
secondary end point studied was 30-day mortality, which attribute the survival benefit in this group to surgical
did not differ between the groups (LRT, 1.4%; ST, 1.5%). intervention because this group inherently had more
Although these findings challenge current standards of favorable disease. Soran et al.9 have not provided definitive
care for patients with de novo stage 4 breast cancer in terms support for surgical intervention as a means to improve
of limiting surgical intervention to palliation, this trial had survival for patients who present with de novo metastatic
several significant limitations. The study design was based breast cancer. Therefore, these cases should continue to be
on the assumption of a 3-year OS of 35% in the LRT group discussed in a multidisciplinary fashion.
and 17% in the ST group from literature published before In the United States, overall breast cancer death rates, as
2007. As recognized by the authors of this study, recent reported by the American Cancer Society, declined rapidly
improvements in systemic treatment, including targeted from 2006 to 2015, with a total decline of 39% through
therapy, have markedly increased the 3-year survival for 2015, and this is largely attributed to both early screening
patients. With better systemic therapy regimens, the per- and improved systemic therapy (mainly the introduction of
ceived surgical benefits in terms of median survival rates targeted therapies such as endocrine and HER2-based
reported by Soran et al.9 may be diminished. Furthermore, regimens). As such, it would be difficult not to initiate
stratification factors such as patient age, tumor size, his- systemic therapy up front for patients with de novo meta-
tologic grade/type, and receptor status, which are critical to static breast cancer. One such study, which addresses the
randomization, were not planned. Instead, Soran et al.9 role of systemic therapy followed by surgical intervention
De Novo Stage 4 Metastatic Breast Cancer

in this subgroup, is the United States-based Translational 2. Babiera GV, Rao R, Feng L, et al. Effect of primary tumor
Breast Cancer Research Consortium (TBCRC) 013 trial, a extirpation in breast cancer patients who present with stage IV
disease and an intact primary tumor. Ann Surg Oncol.
prospective registry trial that enrolled 112 patients with an 2006;13:776–82.
intact primary tumor between 2009 and 2012 at 14 insti- 3. Rapiti E, Verkooijen HM, Vlastos G, et al. Complete excision of
tutions.14 After the patients had received first-line therapy primary breast tumor improves survival of patients with meta-
by their treating providers, all the responders (94 patients, static breast cancer at diagnosis. J Clin Oncol. 2006;24:2743–9.
4. Gnerlich J, Jeffe DB, Deshpande AD, Beers C, Zander C, Mar-
85%) were considered for elective surgery. A multivariable genthaler JA. Surgical removal of the primary tumor increases
analysis, with censorship for survival at 6 months, showed overall survival in patients with metastatic breast cancer: analysis
that surgery of the primary cancer did not improve overall of the 1988–2003 SEER data. Ann Surg Oncol. 2007;14:2187–94.
survival among the responders, who had a median survival 5. Fields RC, Jeffe DB, Trinkaus K, et al. Surgical resection of the
primary tumor is associated with increased long-term survival in
of 71 months versus 65 months for the patients without patients with stage IV breast cancer after controlling for site of
surgery (or 30-month survival rates of 77 and 76%, metastasis. Ann Surg Oncol. 2007;14:3345–51.
respectively; p = 0.85). These initial findings of the 6. Bafford AC, Burstein HJ, Barkley CR, et al. Breast surgery in
TBCRC 013 study must be addressed because the benefits stage IV breast cancer: impact of staging and patient selection on
overall survival. Breast Cancer Res Treat. 2009;115:7–12.
outlined by Soran et al.9 are for patients who are treatment 7. Dominici L, Najita J, Hughes M, et al. Surgery of the primary
naı̈ve before surgery. tumor does not improve survival in stage IV breast cancer. Breast
Given the rapid advances in systemic therapy, it is dif- Cancer Res Treat. 2011;129:459–65.
ficult to envision not initiating patients on a first-line 8. Cady B, Nathan NR, Michaelson JS, Golshan M, Smith BL.
Matched pair analyses of stage IV breast cancer with or without
systemic therapy before surgery, thereby rendering the resection of primary breast site. Ann Surg Oncol.
findings of Soran et al.9 less relevant in this clinical setting. 2008;15:3384–95.
As such, we await the findings of two additional prospec- 9. Soran, A., Ozmen, V., Ozbas, S. et al. Randomized trial com-
tive randomized trials (Eastern Cooperative Oncology paring resection of primary tumor with no surgery in stage IV
breast cancer at presentation: protocol MF07-01. Ann Surg Oncol.
Group [ECOG] 2108 and Japan Clinical Oncology Group 2018. https://doi.org/10.1245/s10434-018-6494-6.
[JCOG] 1017) to help add clarity to this controversy. In 10. Badwe R, Parmar V, Hawaldar R, et al. Surgical removal of the
ECOG 2108, patients with disease who do not progress primary breast tumor and axillary lymph nodes in women with
during initial systemic therapy are randomized to continued metastatic breast cancer at first presentation: a randomized con-
trolled trial. In: Presented at the 2013 San Antonio Breast Cancer
systemic therapy versus surgery with intention for negative symposium, 10–14 December 2013, San Antonio, TX. Abstract
surgical margins, either through breast-conserving therapy S2-02.
(BCT) involving lumpectomy and radiation therapy or total 11. Badwe R, Hawaldar R, Nair N, et al. Locoregional treatment
mastectomy with or without radiation. Similarly JCOG versus no treatment of the primary tumour in metastatic breast
cancer: an open-label randomised controlled trial. Lancet Oncol.
1017 is studying patients with stage 4 disease who receive 2015;16:1380–8.
primary systemic therapy according to their tumor subtype, 12. Harris E, Barry M, Kell MR. Meta-analysis to determine if sur-
followed by randomization to surgery plus systemic ther- gical resection of the primary tumour in the setting of stage IV
apy or to systemic therapy alone. Until the results of these breast cancer impacts on survival. Ann Surg Oncol.
2013;20:2828–34.
additional studies are finalized, patients with de novo 13. Petrelli F, Barni S. Surgery of primary tumors in stage IV breast
metastatic breast cancer should not be managed with sur- cancer: an updated meta-analysis of published studies with meta-
gical intervention as a means to improve survival. regression. Med Oncol. 2012;29:3282–90.
14. King TA, Lyman J, Gonen M, et al: A prospective analysis of
surgery and survival in stage IV breast cancer (TBCRC 013).
REFERENCES 2016 ASCO Annual Meeting. Abstract 1006. Presented at Chi-
cago Illinois, 4 June 2016.
1. Khan SA, Stewart AK, Morrow M. Does aggressive local therapy
improve survival in metastatic breast cancer? Surgery.
2002;132:620–6; discussion 626–7.