Responsiveness of adjacent ductal carcinoma in situ and changes in HER2 status after neoadjuvant chemotherapy/trastuzumab treatment in early breast cancer—results from the GeparQuattro study (GBG 40)

Abstract

Adjacent ductal carcinoma in situ (DCIS) is found in approximately 45% of invasive ductal carcinomas (IDC) of the breast. Pure DCIS overexpresses HER2 in approximately 45%. There is uncertainty whether adjacent DCIS impacts on the response to neoadjuvant chemotherapy and trastuzumab as well as whether HER2 expression in IDC component or adjacent DCIS changes throughout treatment. Core biopsies and surgical tissue from participants of the GeparQuattro study with HER2-positive IDC were centrally examined for the area of invasive ductal component and adjacent DCIS before and after receiving neoadjuvant anthracycline-taxane-trastuzumab containing chemotherapy. HER2 overexpression in IDC and adjacent DCIS was quantified separately by immunohistochemistry using the Ventana automated staining system. Pathological complete response (pCR) was defined as no residual invasive or non-invasive tumor tissue. Fifty-nine (37.3%) of 158 IDCs presented with adjacent DCIS at diagnosis. These tumors showed lower regression grades than pure IDC (P = 0.033). The presence of adjacent DCIS was an independent negative predictor of pCR [odds ratio 0.42 (95% CI 0.2-0.9), P = 0.027]. Adjacent DCIS area decreased from pre-treatment to surgery (r = 0.205) with 30 (50.8%) IDCs with adjacent DCIS showing complete eradication of adjacent DCIS. HER2 status of adjacent DCIS was highly correlated with HER2 status of IDC component before (r = 0.892) and after treatment (r = 0.676). Degree of HER2 overexpression of the IDC component decreased in 16 (33.3%) out of 49 patients without a pCR. These 16 IDCs showed lower RGs compared to the 33 IDCs with unchanged HER2 expression (P = 0.055). HER2-positive IDCs with adjacent DCIS is less responsive to neoadjuvant chemotherapy and trastuzumab compared to pure IDC. However, complete eradication of adjacent DCIS is frequently observed. HER2-overexpression of the invasive ductal component decreases in a subset of tumors, which showed less tumor regression.

Breast cancer during follow-up and progression – A population based cohort on new cancers and changed biology

“…Our results demonstrate a higher proportion of patients losing ER from the primary breast cancer to the relapse, among the patients who had received adjuvant endocrine therapy alone or in combination with chemotherapy, however small numbers in some groups ( Table 2). This finding is in line with previous studies demonstrating that neoadjuvant therapy such as chemotherapy, trastuzumab and endocrine therapy seems to affect the receptor status of the primary tumour [11,12]. In addition, loss of ER has been observed following treatment with endocrine therapy in the advanced settings [13].…”

Effect of Metformin on Breast Ductal Carcinoma In Situ Proliferation in a Randomized Presurgical Trial

“…These results extend and further complement our prior findings in HER2þve invasive disease, where metformin significantly reduced the Ki-67 increase observed in the placebo arm after 4 week between biopsy and surgery (15,34). In addition, the number of adjacent HER2þve DCIS was larger than that of HER2þve invasive cancer, in line with prior data (35), indicating that our findings do not simply replicate results in HER2þve invasive disease (15). Indeed, the large magnitude of the posttreatment Ki-67 difference between arms strongly suggests that HER2þve DCIS is particularly sensitive to the antiproliferative effect of metformin, which has important preventive implications because HER2 overexpression or gene amplification is involved in the transition from DCIS to invasive disease (36) and predicts the presence of invasive foci (37).…”

Incorporating Agents that Target HER2 in the Neoadjuvant Setting

“…In a histopathological study, ductal carcinoma in situ adjacent to invasive HER2-positive breast cancer was associated with a lower pCR rate to chemotherapy with trastuzumab [37].…”