Biomarker Discordances and Alterations Observed in Breast Cancer Treated with Neoadjuvant Chemotherapy: Causes, Frequencies, and Clinical Significances

Abstract

Purpose: Biomarker discordances and alterations can be encountered between tru-cut biopsy and residual tumor in breast cancer treated with neoadjuvant chemotherapy (NACTx). We aimed to investigate the effect of NACTx on major biomarker expression (ER, PR, HER2, Ki-67) and tumor grade, the frequency and causes of receptor discordances, and the clinical significance of changes in terms of adjuvant therapy need and chemosensitivity. Methods: In this retrospective study, ER, PR, HER2, and Ki-67 expression and tumor grades were compared between pre- and post-NACTx tumor samples using the Wilcoxon signed-rank test. The frequencies of receptor discordances and the need for new adjuvant therapy due to discordances were calculated. The effect of patient and tumor characteristics and NACTx regimens on discordances was investigated using multivariate analysis. Using histopathological examinations, residual tumors were divided into chemotherapy-responsive and chemotherapy-unresponsive tumors. Biomarker changes in both groups were analyzed for predictability of chemosensitivity. Results: Of the 169 patients who received NACTx, 102 patients having enough residual tumors in the surgical pathology specimen were enrolled in the study. Histopathologically, about 70% of tumors were partially responsive to NACTx and 30% were unresponsive (chemo-resistant). The concordance and discordance rates were 95.1% versus 4.9% for ER (p = 0.180), 97.1% versus 2.9% for PR (p = 0.083), and 89.2% versus 10.8% for HER2 (p = 0.763), respectively. In addition, 15% of hormone receptor (HR)-negative patients became HR(+) and 5.7% of HER2(−) patients became HER2(+) in the residual tumors, requiring adjuvant endocrine or anti-HER2 therapy. In particular, 18% of triple-negative patients became HR(+) and 12% became HER2(+). HER2 loss was detected in 40% of HER2(+) patients. Multivariate logistic regression analysis revealed that lower estrogen expression (p = 0.046), a smaller tumor size (p = 0.029), and anti-HER2 therapy (p < 0.001) have independent efficacy on ER discordance, PR discordance, and HER2 discordance, respectively. Ki-67 and PR expression significantly decreased in chemotherapy-responsive tumors (p = 0.001 and p = 0.004), and the tumor grade increased in chemotherapy-unresponsive tumors (p = 0.034). Conclusions: Approximately 3–5% of HR discordance and about 10% of HER2 discordance can be observed in breast cancer after currently used NACTx regimens. Discordances are bi-directional (from positive to negative and vice versa), and their causes are multifactorial; they should be assessed accordingly. The NACTx effect alone cannot explain observed discordances but can cause biomarker alterations. The change in receptor status from positive to negative, especially HER2 loss, is mainly associated with the NACTx effect. However, the shift from negative to positive is thought to be primarily related to intratumoral heterogeneity. Receptor statuses becoming positive are of more clinical importance due to adjuvant therapy requirements. Biomarker alterations in PR, Ki-67, and tumor grade can provide predictive information about tumor chemosensitivity.

Use of ultrasound imaging Omics in predicting molecular typing and assessing the risk of postoperative recurrence in breast cancer

“…This discrepancy may stem from variations in immunohistochemistry results within different locations of the same cancer focus, exhibiting differing proportions. Studies indicate that receptor status may undergo changes after neoadjuvant treatment, showcasing inconsistencies of approximately 3–5% in hormone receptor (HR) status and 10% in HER-2 status in breast cancers treated with current neoadjuvant regimens [ 19 ]. Studies emphasize the prognostic implications of changes in immunohistochemistry post-treatment, recommending the retesting of biomarkers following neoadjuvant treatment or upon the development of drug resistance [ 20 , 21 ].…”

Nomograms for Predicting Disease-Free Survival Based on Core Needle Biopsy and Surgical Specimens in Female Breast Cancer Patients with Non-Pathological Complete Response to Neoadjuvant Chemotherapy

“…Alterations in ER, PR, HER2, Ki67, and p53 have been reported following NAC treatment, with widely varying results from series to series [ 18 , 19 , 21 , 35 , 36 ]. Considering that these biomarkers may change after NAC, we included ER, PR, HER2, Ki67, and p53 both before and after treatment in the pre-NAC and post-NAC multivariate analysis, respectively.…”

“…The purpose of this study was to fill this research gap by developing and evaluating novel nomograms for predicting disease-free survival (DFS) based on core needle biopsy and surgical specimens in female BC patients with a non-pCR to NAC. A biopsy at diagnosis and post-NAC residual tumors in patients without a pCR can show discrepancies in receptor status (from negative to positive or vice versa) and changes in biomarker expression [ 18 , 19 ]. Discordances in ER, PR, HER2, Ki67, and p53 can indicate chemosensitivity or chemoresistance as well as have clinical implications for the prognosis and adjuvant therapy [ 18 , 20 , 21 , 22 ].…”

“…A biopsy at diagnosis and post-NAC residual tumors in patients without a pCR can show discrepancies in receptor status (from negative to positive or vice versa) and changes in biomarker expression [ 18 , 19 ]. Discordances in ER, PR, HER2, Ki67, and p53 can indicate chemosensitivity or chemoresistance as well as have clinical implications for the prognosis and adjuvant therapy [ 18 , 20 , 21 , 22 ]. Therefore, changes in biomarkers after NAC were considered in this study.…”

Unveiling the Immune Microenvironment’s Role in Breast Cancer: A Glimpse into Promising Frontiers

“…This effect has been observed in different BC subtypes, including HER2+ and TNBC [3,69,70]. In HER2+ malignancies, high TIL levels have been linked to altered chemosensitivity and increased adjuvant trastuzumab therapy efficacy [71]. Regarding how lymphocyte infiltration impacts prognoses and therapy prediction in patients with ER+/HER2 malignancies, there is, however, a paucity of data [72].…”