Abstract PO1-24-03: The clinicopathological and prognostic significance of HER2-low breast cancer: A comparative analysis between HER2-low and HER2-zero subtypes

Abstract Background: HER2-low breast cancer (BC) is a newly defined subset of HER2-negative BC that has a HER2 immunohistochemical (IHC)-1+ or 2+/ISH negative phenotype. Recent clinical trials have demonstrated the clinical benefits of novel HER2 directing ADCs in treating this group. It is uncertain whether HER2-low BC represents a distinct biological/clinical subgroup or if the HER2-low categorization has any prognostic significance. We retrospectively investigated the clinicopathological and prognostic significance of HER2-low BC and compared it with HER2-0 BC. Methods: Primary BC patients who underwent surgery from January 2000 to March 2023 were enrolled in this retrospective study. A total of 10,215 invasive BC cases with Stage I-III were analyzed. The HER2 status was divided into 3 groups: HER2-0, HER2-low, and HER2-positive (3+ or 2+ with positive ISH). The clinicopathological factors investigated were age, nodal status, tumor size, nuclear grade (NG), ER/PgR (cutoff points; 1% and 10%), and the Ki-67 index value (cutoff points: 15% and 30%). The pCR rate in patients who underwent neoadjuvant chemotherapy (NAC) was examined. The disease-free (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method and tested with the log-rank procedure. Uni- and multivariate analyses for recurrent factors were performed using the Cox proportional hazard model. Results: 1. The HER2 status was classified as follows; HER2-0 in 1,227 cases (12.0%), HER2-low in 7,209 cases (70.6%), and HER2-positive in 1,779 cases (17.4%). In the recurrent cases, HER2-low was observed in 648 cases (66.1%), and in cases treated with NAC, HER2-low was observed in 544 cases (52.7%). 2. The HER2 status significantly correlated with age, tumor size, lymph nodal status, ER, PgR, NG, and the Ki-67 index value. A comparison between HER2-low and HER2-0 revealed that patients with HER2-low tumors were significantly more likely to be under 50 years of age and had more positive nodes. Moreover, HER2-low was significantly associated with positive ER/PgR, lower NG, and lower Ki-67 index values. 3. There was no significant difference in terms of DFS between the three HER2 groups. However, a difference was observed between the three groups in terms of OS. HER2-0 had the lowest OS rate. Moreover, there was a significant difference in OS after recurrence between HER2-0 and HER2-low. 4. When the DFS for the ER status was examined, a significant difference between the HER2 status in cases with ER 1.0% and ER10% was observed. Moreover, the DFS in the HER2-low cases was equivalent to the DFS in the HER2-0 cases. However, the DFS in HER2-low was lower in the ER 1-10% group. Although all the HER2 groups showed a significant difference in OS, HER2-low in the ER 1-10% group had the lowest OS, and HER2-0 in the ER10% group had the lowest OS and was significantly different from HER2-low in the same group. 5. A multivariate analysis revealed that there was no significant difference between HER2-low and HER2-0 as a prognostic factor after recurrence. 6. The pCR rate for NAC was lowest in the HER2-low group, and the pCR rate in the HER2-low group was significantly lower than the HER2-0 group. 7. The DFS after NAC was significantly better in all the pCR cases, regardless of the HER2 status. However, the DFS was significantly lower in the HER2-low non-pCR cases. Conclusion: HER2-low accounted for 70% of the cases. There were more cases with positive ER/PgR, lower NG, and lower Ki-67 index values in the HER2-low group. The HER2-low group had a significantly better OS than the HER2-0 group. However, the response to NAC was low in the HER2-low group and this group had the poorest prognosis among all the non-pCR cases. These findings indicate that HER2-low has a different biology and prognosis compared to HER2-0 and it may be a new subtype. Citation Format: Reiki Nishimura, Yoshitaka Fujiki, Tetsuhiko Taira, Toshiko Miyaki, Shuichi Kanemitsu, Daisuke Yotsumoto, Megumi Teraoka, Junko Kawano, Naomi Gondo, Reiko Mitsueda, Shinichi Baba, Yasuyo Ohi, Yoshiaki Rai, Yoshiaki Sagara, Yasuaki Sagara. The clinicopathological and prognostic significance of HER2-low breast cancer: A comparative analysis between HER2-low and HER2-zero subtypes abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-24-03.