Meeting NewsPerspective

Surgery prolongs survival in HER2-positive advanced breast cancer

Photo of Sharon Lum 
Sharon Lum
Photo of Ross Mudgway 
Ross Mudgway

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

References:

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.

Photo of Sharon Lum 
Sharon Lum
Photo of Ross Mudgway 
Ross Mudgway

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.

PAGE BREAK

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).

PAGE BREAK

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

References:

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.

    Perspective
    Richard J. Bleicher

    Richard J. Bleicher

    Previous literature suggests that surgery may benefit patients who have metastatic breast cancer; this study supports the benefit in patients with HER2-positive breast cancer. The concept is not new, but it does offer additional data to support the idea that resecting the primary tumor may provide a survival advantage.

    However, there are prospective trials from overseas that have conflicting results about the issue, so we eagerly await the results of the ECOG 2108 trial, which prospectively randomly assigned patients who have metastatic disease to standard surgery or no surgery.

    References:

    Gnerlich J, et al. Ann Surg Oncol. 2007;doi:10.1245/s10434-007-9438-0.

    Khan SA, et al. Surgery. 2002;132(4):620-626.

    Vohra NA, et al. Breast J. 2018doi:10.1111/tbj.13005.

    • Richard J. Bleicher, MD, FACS
    • Fox Chase Cancer Center

    Disclosures: Bleicher reports no relevant financial disclosures.

    Perspective
    Lisa Newman

    Lisa Newman

    Historically, surgeons have been appropriately reluctant to operate on the breast of a woman with documented stage IV breast cancer because the metastatic disease is clearly the biggest threat to that patient’s life. Also, there was a theoretical concern that if you operated on the breast it could disrupt an immunologic balance between the cancerous foci in the woman’s body, resulting in progression of the distant organ metastases. We would therefore only consider breast surgery as a palliative strategy in stage IV breast cancer, to improve quality of life in a patient with an ulcerated, bleeding or fungating tumor that could not be controlled with systemic therapy.

    Happily, however, advances in systemic therapy for breast cancer — particularly with targeted therapeutic approaches — have resulted in prolonged survival rates for women with stage IV breast cancer over the past few decades. We have therefore seen a resurgence of interest in breast surgery for these patients, as a mechanism that might contribute to decreasing the total body burden of disease.

    Several retrospective studies, such as this one from the National Cancer Database, have indeed shown an advantage to operating on the breast in women with known metastatic breast cancer. A recurring theme of many of these retrospective studies has been evidence of selection bias — the women referred for surgery and those who appeared to benefit from surgery were often younger/healthier women, they tended to be patients with fewer metastatic foci, patients with bone-only metastases, and women with evidence of response to systemic therapy.

    This study demonstrated that stage IV breast cancer patients with HER2-overexpressing tumors represented another subset of patients experiencing an outcome advantage if they underwent breast surgery. This finding reinforces the concept that systemic therapy is essential for these patients; targeted anti-HER2 therapy has dramatically improved outcomes for patients with HER2-overexpressing phenotypes.

    It will be very important as we move forward in attempting to identify women who might benefit from surgery (despite the presence of metastatic disease), to make sure that we have some objective evidence of response to systemic therapy. For most women with stage IV breast cancer, it would be inappropriate to offer them surgery first; it is preferable to monitor their response to primary systemic therapy suited to their disease phenotype. If the patient appears to be responding to systemic therapy then it might be appropriate to consider surgery to resect the disease in the breast. The alternative perspective, of course, is that effective systemic therapy is likely to be controlling the locoregional disease as well as the distant organ metastases, leaving the benefits of surgery difficult to estimate. Some patients will choose to undergo breast surgery because they perceive emotional or psychological value associated with definitive operative resection.

    These discussions of elective breast surgery for stage IV disease — in the absence of locoregional disease that is inadequately controlled by systemic therapy — are difficult. We must be frank and honest with our patients regarding the possible risks vs. benefits of surgery. We must consider the fitness of the patient with regard to tolerating general anesthesia — especially if the patient is considering a prolonged operation involving breast reconstruction — and we must be sure that the patient clearly understands the lack of any definitive evidence that surgery will contribute an survival advantage. Lastly, it is essential that the patient understand the need for ongoing systemic therapy after the surgery has been completed. Processing these issues is a substantial burden to place on the shoulders of patients that are already at a very vulnerable time in their lives, but it is critical for them to be a part of the decision-making process.

    The benefits of anti-HER2 therapy for patients will all stages of HER2-overexpressing breast cancer definitely represent an exciting advance in breast cancer management. Although several questions remain unresolved regarding optimal selection of stage IV breast cancer patients that might benefit from surgery to the breast, this study suggests that HER2 overexpression might be a factor that should be taken into consideration.

    • Lisa Newman, MD, MPH
    • Chief of Breast Surgery at Weill Cornell Medicine and NewYork-Presbyterian

    Disclosures: Newman reports no relevant financial disclosures.

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