Sustained HER2 Positivity May Correlate With Better Outcomes Compared With HER2 Loss in Breast Cancer

In patients with breast cancer, who were predominantly hormone receptor–positive, 37.8% had a conversion to HER2-positive status that led to significant benefit from frontline treatment with taxane-trastuzumab (Herceptin) with or without pertuzumab (Perjeta), according to a retrospective study published in Breast Cancer Research and Treatment.

Contrary to those with HER2 conversion, those with HER2 loss did not derive significant benefit from the frontline combination as hypothesized by the study investigators. The primary objective when exploring this hypothesis was determining the efficacy of HER2 inhibitors based on HER2 concordance between primary and metastatic breast cancer tissue. The primary end point of the study was progression-free survival (PFS). In addition, overall survival (OS) in patients dependent on the dynamic HER2 status was assessed.

Using an institutional database from the University Hospital UZ Leuven in Belgium, women who received trastuzumab in the neoadjuvant or metastatic setting for a primary or secondary breast tumor were included in the analysis. Patients were required to have a primary or metastatic lesion and determination of HER2 status on both biopsies. HER2 status was confirmed in patients by immunohistochemistry and fluorescence in situ hybridization. Guidelines from the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) were followed to identify HER2-positive individuals during the analysis.

To conduct retrospective analysis, patients were biopsied if they had a poor response to therapy and if they were included in a clinical trial. Biopsies were collected at the start and stop of various lines of therapy. Then, to assess survival outcomes, investigators led by Elisa Van Raemdonck, MD, PhD, utilized the Kaplan-Meier method.

Between January 2002 and September 2017, 1100 patients were treated with trastuzumab at the institution. Of the patients treated, 74 were tested for HER2 status, and it was discovered that 22 patients had synchronous metastatic disease, and 52 patients had metachronous disease.

The results showed that on treatment with taxane-trastuzumab with or without pertuzumab, patients who were positive for HER2 and stayed positive had a median PFS of 9.0 months (95% CI, 7.0-12.0). In the group of patients who were HER2-positive and had HER2 loss, the median PFS was 5.5 months (95% CI, 1.0-7.0). Finally, in the group of patients who were initially negative for HER2 and became positive, the median PFS was 14.0 months (95% CI, 2.0—not estimable). The corrected P-value for the difference between the 3 groups was 0.02.

Other patients who were treated with trastuzumab emtansine (T‑DM1; Kadcyla) had a median PFS of 6.0 months (95% CI, 4.0-8.0) if they maintained their HER2-positive status, and a median PFS of 1.5 months (95% CI, 1.0-2.0) if they started off with HER2-positive disease then had HER2 loss. In patients who were HER2-negative at the start of the study and later became HER2-positive, the median PFS was only 1 month (95% CI, 1.0-5.0). Comparing the 3 groups, the P-value for the difference was .02.

A third arm was treated with the combination of capecitabine and lapatinib (Tykerb), and among those who had consistent HER2 positivity, the median PFS was 4 months (95% CI, 2.0-7.0). Patients who were initially positive and experienced HER2 loss had a median PFS of 1.5 months (95% CI, 1.0-2.0), and those who were negative and became positive had a median PFS of 2.0 months (95% CI, 1.0-5.0).

The results also showed a significant association with OS in the 3 groups by HER2 status (HR, 0.79; 95% CI, 0.356-1.738). Patients who were positive and had HER2 loss appeared to have worse outcomes (HR, 0.15; 95% CI, 0.06-0.38) compared with the other 2 groups (HR, 0.19; 95% CI, 0.08-0.44).

“To the best of our knowledge, our study is the first evaluating PFS using HER2 inhibitors and chemotherapy in metastatic breast cancer by HER2 concordance. Our results show that patients with a negative conversion of the HER2 status had a significantly shorter PFS using HER2 inhibitors and chemotherapy, compared to patients with concordant HER2 status. These findings are significant for the combined therapy taxane/trastuzumab and T-DM1, but insignificant for treatment with lapatinib and capecitabine,” wrote Raemdonck et al.

Overall, the analysis showed that conversion to HER2 status occurred in 28 out of 74 cases and was most notable in the subgroup of patients who were also hormone receptor–positive. The conversion to HER2 status contributed to the receipt of substantial benefit from frontline HER2 inhibition. The findings underscore the importance of performing biopsies on metastatic lesions to inform therapy choice.

_Reference:

_{Raemdonck EV, Floris G, Bertloot P, et al. Efficacy of anti‑HER2 therapy in metastatic breast cancer by discordance of HER2 expression between primary and metastatic breast cancer. Breast Cancer Research and Treatment. 2021;185:183-194. doi:10.1007/s10549-020-05935-5}