In the last two decades, the introduction of anti-HER2 agents had revolutionized the treatment of HER2 positive breast cancer patients impressively10. Besides trastuzumab, addition or substitution of new novel anti-HER2 regimens were common in clinical practice, accompanied with increased cost and toxicity11. Therefore, it is important for clinicians to identify HER2vpositive patients at high risk of recurrence or death and monitor therapeutic strategies.
Our study discovered prognostic factors for the 2-year survival outcome of HER2 positive breast cancer patients. Based on the factors, we built a prognostic model. Emerging evidence indicated that the first two years were particularly important in HER2-positive breast cancer treatment. Although trastuzumab plus standard chemotherapy for early-stage HER2 positive breast cancer was recommended by National Comprehensive Cancer Network guideline12, new recurrences could be observed during or within 12 months after 1-year adjuvant trastuzumab treatment, which was defined as trastuzumab resistance13,14. In clinical trials, the results showed that approximately 10-15% of early HER2 positive breast cancer patients receiving trastuzumab treatment experienced disease progression in the first two years and then the rate increased slowly and finally reached a plateau of 20-25% in the following years3,5. Different from HER2 positive subtype, the results of clinical trials showed that for triple-negative breast cancer, the DFS and OS rates remained high in the first 12 months and then kept decreasing slowly in the following years15,16. Comparatively, patients with HR+/HER2- had high 5-year DFS or BCSS rates17,18 though recurrences can occur even several decades later after primary diagnosis18. These data called for more attention to the prognosis in the first two years of the treatment for HER2-positive early breast cancer patients.
Therefore, we chose to analyzed potential predictive factors for the 2-year BCSS in HER2 positive early breast cancer. Age, ER status, PR status, histologic type, T stage and N stage were found significantly associated with HER2 positive breast cancer prognosis. ER and PR positivity were associated with better BCSS, which was in agreement with previous retrospective studies19,20. The favorable effects of ER or PR positivity on the survival outcome of HER2 positive breast cancer patients were also observed when the OS or DFS rates were compared between HR positive and HR negative subgroups in clinical trials3,5,6,8. The histologic grade was commonly recommended as a predictor for breast cancer prognosis21. However, our study showed that it might be less valuable when predicting the very early survival outcome of HER2 positive subtype. The majority of HER2 positive tumors presented with histologic grades II/III and we didn’t find statistically important impact of tumor grade on survival outcome of HER2 positive patients. This was also concordant with previous knowledge20. The effect of different pathologic types on the short-term survival outcome was generally overlooked before. Here, we found it necessary to classify the histologic type into two categories to improve the predictive ability.
Nomogram is a well-developed graphical model for cancer prognosis22. It emphasizes the magnitude of the effect of each predictor and makes the integration more convenient to read and use. Data source of our nomogram was derived from SEER database which covered about 34.6% of the U.S. population23, making the model more applicable. All of the predictors in our nomogram model were basic clinicopathologic characteristics which could be collected easily during the process of diagnosis and treatment, so that it would be used conveniently in clinical practice. According to the nomogram, patients at high risk had increasing chances experiencing BCSS events and therapeutic escalation, including concomitant trastuzumab and pertuzumab6 or sequential trastuzumab and neratinib7,24. On the other hand, patients with low scores were less risky. Proper de-escalated therapy, such as strategies in the APT trial, could lighten the financial burdens for patients and avoid adverse effects without therapeutic effect compromise25.
We should admit that there were some limitations of the nomogram model. We could not obtain the details about whether patients derived from SEER database received anti-HER2 treatment and our model was based on the whole population without regard to anti-HER2 drug use. To solve this problem, we validated our model in patients from SJTU-BCDB. Although the number of the 2-year NCSS events was small in validation cohort, the nomogram model still showed good predictive ability. In addition, because the validation was based on one single institution in China, whether the nomogram could be generally applied should be further investigated.
In conclusion, we constructed a novel nomogram with great potential to help clinicians with making therapeutic strategies for non-metastatic HER2 positive breast cancer patients. Still, our model needed to be tested in various populations to gain greater reliance.