Surgery Linked With Improved OS in HER2+ Advanced Breast Cancer

Ross Mudgway

Primary tumor surgery for patients with stage IV HER2-positive breast cancer is associated with an improvement in overall survival (OS), according to results of a retrospective cohort review presented at the 2019 AACR Annual Meeting.

At a median follow-up of 21.2 months (range, 0-52), the median OS for patients who had surgery was 25 months compared with 18 months in those who did not undergo resection, leading to a 44% reduction in the risk of death (HR, 0.56; 95% CI, 0.40-0.77; P = .0004).

“In the current era where HER2-targeted therapy has led to improved survival for HER2-positive metastatic breast cancer, our study suggests that surgery may be associated with even better survival for the HER2-positive stage IV breast cancer population,” said lead study author Ross Mudgway, a medical student at the University of California, Riverside School of Medicine. “Our results suggest that providers must consider patients individually when considering surgery and be aware that disparities in who receives surgery exist and should be addressed.”

Currently, there is no standard surgical treatment for patients with stage IV breast cancer, Mudgway said; this patient population typically receives systemic therapy, and radiation or surgery may occasionally be used for palliative care.

Prior data evaluating the survival benefit of primary breast cancer surgery have been mixed, he said, citing one phase III trial that demonstrated no benefit² and another, the MF07-01 study,³ which showed that, with longer follow-up, there was an improvement in median survival with primary stage IV breast tumor resection.

With the advent of several systemic therapies that have significantly improved outcomes, such as trastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), and ado-trastuzumab emtansine (T-DM1; Kadcyla), the impact of surgery in this current era of targeted treatments needs to be evaluated, Mudgway said.

In the retrospective cohort review, investigators analyzed data from 2.8 million breast cancers in the National Cancer Database between January 1, 2010, and December 31, 2012. After narrowing down for female patients, those with adenocarcinoma histology, invasive behavior, HER2 positivity, American Joint Committee on Cancer stage IV, exclusion of missing values, had a breast cancer diagnosis between 2010 to 2012, and reported surgery designation—the sum was a final sample of 3231 patients. The primary endpoints were receipt of surgery and OS.

The variables analyzed included age, race/ethnicity, insurance status, Charlson/Deyo score, treatment facility type, annual income, clinical tumor stage, clinical nodal stage, estrogen receptor (ER) status, progesterone receptor (PR) status, number of regional lymph nodes examined, radiation therapy, chemotherapy/immunotherapy (which was used as a surrogate for HER2-targeted therapy), endocrine therapy, site of metastasis, and vital status.

In the overall population (n = 3231), 71.3% of patients were white. More patients had private insurance (45.9%) than Medicare or other government insurance (31.7%), and 22.5% were not insured or on Medicaid. A total of 34.1% of patients were treated in an academic or research facility. Regarding annual income, 30.2% were of highest quartile and 19.2% were of the lowest. Seventy-five percent of patients had visceral metastases. For treatment, 31.8% had radiation, 89.4% had chemotherapy/immunotherapy, 37.7% had endocrine therapy, and 35% of patients underwent surgery.

Factors that attributed to increased likelihood of patients undergoing surgery included those with private insurance (42.3%; odds ratio [OR], 1.93; 95% CI, 1.53-2.42) or with Medicare/other government insurance (30.5%; OR, 1.36; 95% CI, 1.03-1.81). Additionally, patients of a lower income quartile were more likely to receive surgery (34.6%) than of those of the highest (34.4%; OR, 1.45; 95% CI, 1.12-1.87).

Patients who underwent radiation therapy were also more likely to have surgery (47.4%) than those who did not (28.8%; OR, 2.10; 95% CI, 1.76-2.51), as well as those who also received chemotherapy/immunotherapy versus not, at 36.5% and 22.2% (OR, 1.99; 95% CI, 1.47-2.70), respectively. Likewise, patients who received endocrine therapy were also more likely to undergo surgery (41.3%) compared with those who did not receive the treatment (31.3%; OR, 1.73; 95% CI, 1.40-2.14).

Some factors contributed to a decreased chance of patients with stage IV HER2-positive breast cancer undergoing surgery. Patients aged 20 to 39 years had a 44.5% likelihood, compared with 36.9% in those aged 40 to 59 years (OR, 0.75; 95% CI, 0.56-1.00) and 30.9% in those aged ≥60 years (OR, 0.58; 95% CI, 0.42-0.81). African-American patients were less likely (27.7%) compared with white patients (36.9%; OR, 0.68; 95% CI, 0.53-0.87), as were patients who were treated at an academic center (29.1%) versus a community practice (37.1%; OR, 0,67; 95% CI, 0.50-0.89).

Additionally, those with T4 tumors were less likely to undergo surgery (29.9%; OR, 0.67; 95% CI, 0.51-0.80) compared with T3 tumors (31.8%; OR, 0.73; 95% CI, 0.53-0.99) and T0 to T2 (40.2%). For clinical nodal stage, those with N1 disease were least likely to undergo surgery (32.0%; OR, 0.60; 95% CI, 0.48-0.74) compared with N3 (33.8%; OR, 0.67; 95% CI, 0.50-0.89), N2 (34.7%; OR, 0,72; 95% CI, 0.54-0.95), and N0 disease (42.3%).

Factors that were determined to not be associated with likelihood of surgery were Hispanic ethnicity, comorbidities, and site of metastasis; features that were not linked with survival were comorbidities, treatment facility, ER or PR status, and clinical tumor or nodal stage.

However, there were variables linked with decreased survival: African-American patients (HR, 1.39; P = .002), lowest annual income (HR, 1.36; P = .01), visceral metastases (HR, 1.44; P = .0003), and radiation therapy (HR, 1.33; P = .0009). However, other factors were associated with an increase in survival: patients aged 40 to 59 years (HR, 004; P <.0001), having Medicare or other government insurance (HR, 0,36; P <.0001), receiving chemotherapy/immunotherapy (HR, 0.76; P = .008), and receiving endocrine therapy (HR, 0.70; P = .0006).

Mudgway did mention that there were several limitations of this study, as it was retrospective, the targeted therapy was not specified, there was limited comorbidity assessment, and selection bias existed.

Ongoing phase III studies of primary site surgery in stage IV breast cancer should evaluate this further in HER2-positive subsets and specifically with HER2-targeted therapies, Mudgway concluded.

Senior author Sharon Lum, MD, professor in the Department of Surgery-Division of Surgical Oncology and medical director of the Breast Health Center, Loma Linda University, said in a press release, “This suggests that, in addition to standard HER2-targeted medications and other adjuvant therapy, if a woman has stage IV HER2-positive breast cancer, surgery to remove the primary breast tumor should be considered.”

References

1. Mudgway R, Chavez de Paz Villaneva C, Lin AC, et al. The impact of primary tumor surgery on survival in HER2 positive stage IV breast cancer patients in the current era of targeted therapy. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract 4873.
2. 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):1280-1388. doi: 10.1016/S1470-2045(15)00135-7.
3. Soran A, Ozmen V, Ozbas S, et al. Randomized trial comparing resection of primary tumor with no surgery in stage IV breast cancer at presentation: protocol MF07-01. Ann Surg Oncol. 2018;25(11):3141-3149. doi: 10.1245/s10434-018-6494-6.

<<< 2019 AACR Annual Meeting