Surgery prolongs survival in HER2-positive advanced breast cancer
ATLANTA — Primary tumor resection prolonged survival among women with HER2-positive stage IV breast cancer, according to results of a retrospective analysis presented at American Association of Cancer Research Annual Meeting.
Twenty to 30 percent of newly diagnosed stage IV breast cancer cases are positive for HER2, a subtype of breast cancer that historically has had poor outcomes. However, advances in targeted therapy — including use of trastuzumab (Herceptin, Genentech) — have improved outcomes for these patients. Most patients receive systemic chemotherapy, targeted therapy and/or hormonal therapy, but surgery has shown mixed results in clinical trials.
For instance, a large registry study conducted in 2006 suggested a benefit of surgery for stage IV breast cancer. A phase 3 trial conducted in Turkey also showed benefit, but another phase 3 trial in India did not.
“Anecdotally, we observed that many patients with advanced HER2-positive breast cancer have had tremendous responses to the new targeted therapies, and the oncologists were referring them back to surgeons for consideration of local regional therapy,” Sharon Lum, MD, professor in the department of surgery, in the division of surgical oncology, and medical director of the Breast Health Center at Loma Linda University Health, and Ross Mudgway, a medical student at University of California, Riverside School of Medicine, said in a joint statement to HemOnc Today. “Although, traditionally, surgeons have avoided operating on patients with metastatic breast cancer due to the patient’s likelihood of dying of their metastatic disease, these HER2-positive patients seemed to be doing so well that surgery might make sense.”
Patients with HER2-positive disease have been surviving long enough that their primary tumor “became a problem for them,” Lum and Mudgway added.
“However, we did not have any data to support doing surgery in these cases,” they said. “Prior studies have demonstrated mixed results regarding the survival benefit from surgery for stage IV breast cancer, but these were completed prior to routine use of anti-HER2-targeted therapies, so we wanted to further examine the role of surgery in patients with HER2-positive stage IV breast cancer.”
Lum, Mudgway and colleagues used the National Cancer Database to assess the impact of primary tumor resection on survival among these patients in the era of HER2-targeted therapy. Researchers evaluated data from 2010 — at which point mandatory HER2 reporting began — to 2012.
The analysis included 3,231 patients (non-Hispanic white, 71.3%; non-Hispanic black, 18.4%; Hispanic, 5.8%). Twenty-five percent of patients had bone-only metastasis.
Most patients (89.4%) received chemotherapy and immunotherapy, 37.7% received endocrine therapy and 31.8% underwent radiation.
Thirty-five percent (n = 1,130) of patients underwent primary site surgery. These patients were significantly younger than those who did not undergo surgery (56 ± 13.6 years vs. 59.1 ± 13.7 years; P < .0001).
Median follow-up was 21.2 months (range, 0-52).
Researchers compared survival outcomes for patients who did and did not undergo surgery using propensity score matching to lower the likelihood for selection bias, adjusting the data for demographic, tumor and treatment factors.
Results showed that surgery resulted in a 44% improvement in survival compared with no surgery, assuming the majority also had systemic treatment (HR = 0.56; 95% CI, 0.4-0.77).
Lum and Mudgway said they both were and were not surprised by these findings.
“We had a hunch that surgery might be associated with improved survival, as in our clinics, our patients with HER2-positive disease have so many new treatment options and seem to be doing so much better than in years past,” they told HemOnc Today. “We were surprised by the large degree of the effect of surgery associated with improved survival that seemed to be independent of other factors typically associated with outcomes, like patient comorbidities or tumor size.”
Researchers also found that patients were more likely to undergo surgery if they had Medicare/other government insurance (OR = 1.36; 95% CI, 1.03-1.81) or private insurance (OR = 1.93; 95% CI, 1.53-2.42) compared with no insurance or Medicaid; and if they received radiation (OR = 2.1; 95% CI, 1.76-2.51), chemotherapy/immunotherapy (OR = 1.99; 95% CI, 1.47-2.7) or endocrine therapy (OR = 1.73; 95% CI, 1.4-2.14).
Patients who appeared less likely to undergo surgery included non-Hispanic black patients (vs. non-Hispanic white; OR = 0.68; 95% CI, 0.53-0.87) and those treated at an academic or research program (vs. community program; OR = 0.67; 95% CI, 0.5-0.89).
“Academic/research hospitals are more likely to involve patients in clinical trials of new targeted therapies, and hence are less likely to incorporate surgery as a primary modality of treatment in the metastatic setting,” Lum and Mudgway said. “Also, there is only one prospective, randomized clinical trial so far that shows a survival advantage for removing the primary breast tumor when women have metastatic breast cancer. The other prospective trials did not show a benefit of surgery.”
Factors associated with reduced risk for mortality included having Medicare or other government insurance (vs. none or Medicaid; HR = 0.36; P < .001), as well as receiving chemotherapy/immunotherapy (HR = 0.76; P = .008), endocrine therapy (HR = 0.7; P = .0006) or radiation therapy (HR = 1.33; P = .0009).
Non-Hispanic black race/ethnicity was associated with poorer outcomes compared with non-Hispanic white race/ethnicity (HR = 1.39; P = .002), as was having visceral vs. bone-only metastases (HR = 1.44; P = .0003) and being in the lowest vs. highest income quartile (HR = 1.36; P = .01).
The retrospective nature of the analysis serves as a limitation, as women may be more likely to undergo surgery if they are healthier overall.
“It is very possible the results may have been influenced by surgeon preferences to perform surgery or not and, given the retrospective nature of our study, is one of our major limitations,” Lum and Mudgway said. “The National Cancer Database, while extensive, does not contain information that can select for individual surgeon preferences. There are currently ongoing clinical trials that examine this exact question prospectively, and that are including the current targeted therapy regimens. However, we will have to wait several years for preliminary results.”
Overall, these data suggest that, in addition to HER2-targeted therapy and other adjuvant therapy, surgery to remove the primary breast tumor should be considered among women with stage IV HER2-positive breast cancer depending on their response to targeted therapies.
“We hope that our results encourage clinicians to consider surgical treatment in the face of HER2-positive metastatic disease while weighing the risks and potential benefits,” Lum and Mudgway said. – by Alexandra Todak
Babiera GV, et al. Ann Surg Oncol. 2006;13(6):776-782.
Badwe R, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)00135-7.
Mudgway R, et al. Abstract 4873. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
Soran A, et al. Ann Surg Oncol. 2018;doi:10.1245/s10434-018-6494-6.
Disclosures: The authors report no relevant financial disclosures.