Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

Temozolomide (TMZ) is an alkylating agent that has yielded significant benefits and is a current standard agent in the treatment of malignant gliomas. However, its survival benefit remains unsatisfactory. Recently, a synergistic antitumor effect between TMZ and interferon-β (IFN-β) was reported in malignant glioma cells. The Japan Clinical Oncology Group (JCOG) brain tumor study group has recently began a randomized phase II study to evaluate the clinical effectiveness of combination therapy with TMZ and IFN-β in glioblastomas. However, it is not sufficient just to evaluate the mechanisms and establish an experimental basis for rational clinical therapy with IFN-β and TMZ. The precise mechanisms governing the direct effects of IFN-β and a combination of IFN-β and TMZ in gliomas are not yet fully understood. To gain insight into the mechanisms of sensitivity/resistance involving IFN-β and combination therapy with IFN-β and TMZ, and further to identify new marker(s) that could be used clinically to predict the response to such therapy and new target gene(s) for therapies related to malignant glioma patho-genesis, we evaluated the gene expression profiles of human malignant glioma cell lines employing a high-density oligo-nucleotide DNA array, GeneChip. We present a list of the most highly upregulated and downregulated genes which may be involved in conferring a response to IFN-β and synergistic effect between IFN-β and TMZ in malignant gliomas. Although the present study has several limitations, our reported candidate genes could represent not only potential molecular markers but also chemotherapy targets for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance in malignant gliomas.     

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab

Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood–brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.     

Ductal carcinoma in situ of the breast: is breast conserving treatment feasible?

Between 1968 and 1993, 43 cases of ductal carcinoma in situ of the breast (DCIS) were treated. We examined the extent of the cancer using multiple sections of surgical specimens and considered whether or not breast conserving treatment (BCT) is feasible for treatment of DCIS. In nine out of 40 patients (23%), extent of the cancer was classified as grade III, defined as extension over a 2.5-cm margin around the tumor. Among those nine cases, 67% (6/9) had extensive microcalcification on mammography. With respect to the correlation between the tumor size and the extent of the cancer, 29%(5/17) of the cases with a small size tumor, ie, 1.0 cm or less, showed grade III or greater. All tumors with a size of 1.1-2.0 cm showed grade II or lower, and 50%(4/8) of cases with a tumor size of 2.1 cm or more showed grade III or greater. Concerning the relationship between the histological subtype and the extent of the cancer, 22%(2/9) of comedo carcinomas and 23%(7/30) of noncomedo carcinomas showed grade III or greater. The histological extent thus showed no difference between comedo carcinoma and noncomedo carcinoma. It follows that, when BCT performed on DCIS consists of lumpectomy alone, BCT is feasible when the tumor size is 1.1-2.0 cm. without extensive microcalcification on mammography. However, BCT for comedo carcinoma should be approached with caution because of its malignant behavior, although there was no difference in histological extent between comedo and noncomedo carcinoma.     

Invasive ductal carcinoma and invasive lobular carcinoma of breast differ in response following neoadjuvant therapy with epidoxorubicin and docetaxel + G-CSF

Purpose Preoperative chemotherapy in patients with primary breast cancer treated with anthracyclines and taxanes results in high response rates, allowing breast conserving surgery (BCS) in patients primarily not suitable for this procedure. Pathological responses are important prognostic parameters for progression free and overall survival. We questioned the impact of histologic type invasive ductal carcinoma (IDC) versus invasive lobular carcinoma (ILC) on response to primary chemotherapy. Patients and Methods 161 patients with breast cancer received preoperative chemotherapy consisted of epidoxorubicin 75 mg/m² and docetaxel 75 mg/m² administered in combination with granulocyte-colony stimulating factor (G-CSF) on days 3–10 (ED + G). Pathological complete response (pCR), biological markers and type of surgery as well as progression free and overall survival were compared between IDC and ILC. Results Out of 161 patients, 124 patients presented with IDC and 37 with ILC. Patients with ILC were less likely to have a pCR (3% vs. 20%, P < 0.009) and breast conserving surgeries (51% vs. 79%, P < 0.001). Patients with ILC tended to have oestrogen receptor positive tumors (86% vs. 52%, P < 0.0001), HER 2 negative tumors (69% vs. 84%), and lower nuclear grade (nuclear grade 3, 16% vs. 46%, P < 0.001). Patients with ILC tended to have longer time to progression (TTP) (42 months vs. 26 months) and overall survival (69 months vs. 65 months). Conclusions Our results indicate that patients with ILC achieved a lower pCR rate and ineligibility for BCS to preoperative chemotherapy, but this did not result in a survival disadvantage. Because of these results new strategies to achieve a pCR are warranted.     

Down‐regulation of gelsolin expression in human breast ductal carcinoma in situ with and without invasion

Expression of gelsolin, an actin filament regulatory protein, in human breast ductal carcinoma in situ (DCIS) was analyzed by immunohistochemistry using a monoclonal antibody. Formalinfixed paraffinembedded tissues from 59 pure DCIS specimens and 33 DCIS specimens with associated invasive components were evaluated for gelsolin reactivity and compared to eight normal breast cases and 76 invasive breast cancers. The proportion of cases exhibiting negative/low expression of gelsolin in the epithelium was as follows – normal, 0%; pure DCIS, 56%; DCIS associated with invasion, 58% in the DCIS component and 66% in the invasive component; invasive carcinoma, 70%. These data demonstrate that downregulation of gelsolin expression in breast epithelium frequently parallels progression to malignancy. Testing gelsolin expression (normal vs. negative/low levels) in the DCIS lesions for associations with patient age or any of the following histopathologic parameters revealed no significant (95% probability level) correlations – tumor size; pathologic (Van Nuys system) grade; nuclear grade; necrosis; presence of histologic calcifications; presence or type of adjacent benign lesions; architectural histologic pattern; and mammographic extent. Gelsolin loss was more commonly associated with mammographic soft tissue lesions as compared to calcified lesions (P = 0.009). A positive trend of borderline significance (P = 0.06) found in the DCIS with invasion group was a correlation between downregulated gelsolin expression in the DCIS component and size (< versus 15mm) of the invasive tumor. In conclusion, reduced gelsolin protein is detectable in at least half of breast lesions which have progressed to DCIS. The trend between increasing gelsolin loss and malignant progression from normal epithelium to DCIS to invasive breast cancer (P < 0.0001) suggests additional investigation is needed to determine the potential of altered gelsolin expression as a marker for prognosis and for therapeutic interventions in breast cancer.     

TGF-β1 mRNA expression in clinical breast cancer and its relationship to ER mRNA expression

Eighty nine primary breast cancers were investigated forthe expression of TGF-1 and ER mRNA usingPCR of reverse transcribed RNA. PCR products werevalidated using Southern blots and hybridization with radiolabelledcDNA probes. TGF₁ mRNA was found to beexpressed in 56/89 (63%) of the breast cancerswhile ER mRNA was expressed in 23/89 (26%)of the tumours. Using chi-square analysis TGF- mRNAexpression was found to correlate significantly with ERmRNA expression (p < 0.001), in that virtuallyall tumours that expressed ER mRNA co-expressed TGF₁.In tumours that were ER mRNA negative, TGF₁expression was more variable. These results suggest thatduring tumour progression, ER expression is lost morefrequently than is growth factor expression.     

Significance of α9β1 and αvβ6 integrin expression in breast carcinoma

Background  Both α9β1 and αvβ6 integrins have been newly identified from the tracheal epithelium of guinea pig. It has been pointed out that α9β1 functions as a receptor for tenascin-C and osteopontin. As for the ligands of αvβ6, fibronectin and tenascin-C have been identified. It has not been ascertained whether α9β1 and αvβ6 are expressed in normal breast tissue, benign breast lesion or breast carcinoma. Methods  Immunohistochemical staining for α9β1 and αvβ6 was performed in benign breast lesion and breast carcinoma specimens. Western blotting was carried out on 11 breast carcinoma cases. Results  α9β1 was expressed in the cytoplasm of carcinoma cells in 23 of 90 cases (26%) and αvβ6 in the membrane of carcinoma cells in 16 of 90 cases (18%). However, these findings of α9β1 and αvβ6 did not correlate with any clinicopathological factors including the patients’ age, tumor size, histological type of carcinoma, location of carcinoma cells and hormone receptor status. With regard to the histological grade of carcinoma, αvβ6 and α9β1 expression did not statistically correlate, although no expression of αvβ6 was observed in 14 cases of Grade I. On Western-blott analysis strong and weak bands consistent with αvβ6 were noted in the membrane fraction extracted from breast carcinoma cells. On the other hand weak bands consistent with α9 subunit were noted in the whole cell lysates of breast carcinoma cells and very weak or no bands consistent with α9 subunit were noted in the membrane fraction extracted from the breast carcinoma cells. Conclusions  Significance of α9β1 and αvβ6 integrins expression in breast carcinoma was still unknown on clinicopathological examination. The findings of Western blot analysis may indicate that the transportation system of glycoproteins such as integrins to the cell membrane of carcinoma cells is disturbed, although these integrins can be produced.     

Gene expression profiling of ER+ breast cancers: to discriminate the poor prognosis tumors or to define the most suitable treatment?

The cDNA microarray technology allows the simultaneous analysis of all genes expressed in a tumor. This approach has already permitted to propose a molecular classification of breast cancers. Gene expression profiling is now expected to define prognosis signatures claiming the disease outcome as well as signatures predicting response to therapy. The over-expression of a cluster of genes that are implicated in cell cycle and mitosis control has been shown to discriminate a subgroup of ER+ breast cancers exhibiting a poor prognosis. This "proliferation cluster" is shown to be also present in signatures predicting relapse of ER+ breast cancers treated by the anti-estrogen tamoxifen, including the 36-gene classifier that we have recently identified. Consequently, it seems legitimate to wonder if this part of such predictive signature is really specific to the insensitivity to tamoxifen or rather indicates a poor disease outcome whatever the therapy applied. On the other hand, low expression of ER+ related genes and high expression of genes associated to ER- status or low ERalpha levels have been shown to sign a poor prognosis. Whether the estrogen-related genes that are present in our 36-gene classifier specify the clinical disease outcome or are really specific to the response to tamoxifen, remains to be determined. In any case, the specificity of our 36-gene classifier as those predicting the recurrence of ER+ breast cancer under one treatment or another should be demonstrated. In the same way, future studies should define molecular signatures that will be really predictive of the response to the treatment in order to define which one is the most suitable to decrease the risk of relapse of ER+ breast cancers. These studies should be based on neoadjuvant clinical trials that permit to evaluate the response to treatment in an objective manner.     

Gene expression‐based classifications of fibroadenomas and phyllodes tumours of the breast

Fibroepithelial tumors (FTs) of the breast are a heterogeneous group of lesions ranging from fibroadenomas (FAD) to phyllodes tumors (PT) (benign, borderline, malignant). Further understanding of their molecular features and classification might be of clinical value. In this study, we analysed the expression of 105 breast cancer‐related genes, including the 50 genes of the PAM50 intrinsic subtype predictor and 12 genes of the Claudin‐low subtype predictor, in a panel of 75 FTs (34 FADs, 5 juvenile FADs, 20 benign PTs, 5 borderline PTs and 11 malignant PTs) with clinical follow‐up. In addition, we compared the expression profiles of FTs with those of 14 normal breast tissues and 49 primary invasive ductal carcinomas (IDCs). Our results revealed that the levels of expression of all breast cancer‐related genes can discriminate the various groups of FTs, together with normal breast tissues and IDCs (False Discovery Rate < 5%). Among FTs, the levels expression of proliferation‐related genes (e.g. CCNB1 and MKI67) and mesenchymal/epithelial‐related (e.g. CLDN3 and EPCAM) genes were found to be most discriminative. As expected, FADs showed the highest and lowest expression of epithelial‐ and proliferation‐related genes, respectively, whereas malignant PTs showed the opposite expression pattern. Interestingly, the overall profile of benign PTs was found more similar to FADs and normal breast tissues than the rest of tumours, including juvenile FADs. Within the dataset of IDCs and normal breast tissues, the vast majority of FADs, juvenile FADs, benign PTs and borderline PTs were identified as Normal‐like by intrinsic breast cancer subtyping, whereas 7 (63.6%) and 3 (27.3%) malignant PTs were identified as Claudin‐low and Basal‐like, respectively. Finally, we observed that the previously described PAM50 risk of relapse prognostic score better predicted outcome in FTs than the morphological classification, even within PTs‐only. Our results suggest that classification of FTs using gene expression‐based data is feasible and might provide clinically useful biological and prognostic information.     

Does pre-operative breast magnetic resonance imaging in addition to mammography and breast ultrasonography change the operative management of breast carcinoma?

Magnetic resonance imaging (MRI) has been used for the local staging of breast cancer, especially to determine the extent of multiple lesions and to identify occult malignancies. The aim of this study was to evaluate the effect of pre-operative MRI on the surgical treatment of breast cancer. Between January 2006 and May 2007, 535 newly diagnosed breast cancer patients who planned to undergo breast conserving surgery had clinical examinations, bilateral mammography, breast ultrasonography, and breast MRI. The radiologic findings and clinicopathologic data were reviewed retrospectively. Ninety-eight (18.3%) patients had additional lesions, shown as suspicious lesions on breast MRI, but not detected with conventional methods. Eighty-four (15.7%) of these patients had a change in surgical treatment plans based on the MRI results. Forty-seven (8.8%) of the 84 patients had additional malignancies; the other 37 patients (6.9%) had benign lesions. The positive predictive value for MRI-based surgery was 56.0% (47 of 84 patients). During the period of study, the use of pre-operative MRI was increased with time (OR 1.20; 95% CI 1.16–1.23; P < 0.001), but the mastectomy rate did not change significantly (OR 0.98; 95% CI 0.95–1.00; P = 0.059). Multiple factors were analyzed to identify the patients more likely to undergo appropriate and complete surgery based on the additional findings of the pre-operative MRI, but the results were not statistically significant. This research suggests that a pre-operative MRI can potentially lower the rate of incompletely excised malignancies by identifying additional occult cancer prior to surgery and does not lead to an increase in the mastectomy rate; however, because some benign lesions are indistinguishable from suspicious or malignant lesions, excessive surgical procedures are unnecessarily performed in a significant portion of patients. In the future, the criteria for the use of MRI in local staging of breast cancer should be established.     

Patients’ perceptions of gene expression profiling in breast cancer treatment decisions

Introduction

Determining the likely benefit of adjuvant chemotherapy for early-stage breast cancer patients depends on estimating baseline recurrence risk. Gene expression profile (gep) testing of tumours informs risk prediction, but evidence of its clinical utility is limited. We explored patient perceptions of gep testing and the impact of those perceptions on chemotherapy decisions.

Methods

We conducted one focus group (n = 4) and individual interviews (n = 24) with patients who used gep testing, recruited through clinics at two hospitals in Ontario. Data were analyzed using content analysis and constant comparison techniques.

Results

Patients’ understanding of gep testing was variable, and misapprehensions were common. Patients valued the test because it provided them with certainty amidst confusion, with options and a sense of empowerment, and with personalized, authoritative information.They commonly believed that the test was better and fundamentally different from other clinical tests, attributing to it unique power and truth-value. This kind of “magical thinking” was derived from an amplified perception of the test’s validity and patients’ need for reassurance about their treatment choices. Despite misperceptions or magical thinking, gep was widely considered to be the deciding factor in treatment decisions.

Conclusions

Patients tend to overestimate the truth-value of gep testing based on misperceptions of its validity. Our results identify a need to better support patient understanding of the test and its limitations. Findings illustrate the deep emotional investment patients make in gep test results and the impact of that investment on their treatment decisions.     

Do CA125 response criteria overestimate tumour response in second-line treatment of epithelial ovarian carcinoma?

Recent studies indicate that cancer antigen 125 (CA125) response criteria tend to overestimate a tumour reduction measured by standard WHO response criteria in recurrent epithelial ovarian carcinoma. The aim of the study was to validate the recently introduced GCIG (The Gynaecological Cancer Intergroup) CA125 response criteria in predicting a tumour response measured by WHO (World Health Organization) criteria. Changes in CA125 levels (GCIG criteria) were retrospectively compared with alterations in the tumour load (WHO criteria) during second-line chemotherapy with topotecan or paclitaxel-platinum in 124 consecutive patients with recurrent or refractory disease. In patients assessable by both response criteria (n=72), the overall response rate using GCIG CA125 criteria was 57% (95% confidence interval (CI): 45-69%) and significantly higher than the response rate of 39% (95% CI: 28-51%) using WHO response criteria (P=0.045). The GCIG CA125 criteria had a sensitivity of 96% (95% CI: 82-100%), a specificity of 68% (95% CI: 52-81%) and an accuracy of 79% (95% CI: 68-88%) in predicting a response measured by WHO criteria. In conclusion, the GCIG CA125 response criteria seem to overestimate a tumour response by WHO criteria when monitoring the efficacy of second-line chemotherapy with topotecan or paclitaxel-platinum in patients with epithelial ovarian carcinoma.     

Urokinase plasminogen activator system gene expression is increased in human breast carcinoma and its bone metastases — A comparison of normal breast tissue, non-invasive and invasive carcinoma and osseous metastases

The urokinase plasminogen activator (uPA) system has been widely associated with the development of breast carcinoma. However, the role of the urokinase pathway in the development of osseous breast cancer metastases has been largely overlooked. We studied the expression of uPA, urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor type-1 (PAI-1) in human breast carcinomas and their bone metastases, using in situ hybridisation. Studies were performed using paraffin-embedded tissue from 13 ductal carcinomas, 23 invasive ductal carcinomas, five normal breasts and 25 bone metastases. The majority of the tumours examined expressed low to moderate levels of uPA mRNA and low to high levels of uPAR and PAI-1 mRNA, which was predominantly localised to the epithelial tumour cells. There was slight over-expression of uPA and PAI-1 mRNA and a marked increase in uPAR mRNA expression in the malignant tumours compared with benign tissue. Overall, uPAR and PAI-1 mRNA expression was found to be more variable than uPA mRNA, suggesting a possible role of the receptor and inhibitor in the regulation of uPA activity. Increased 1(I) procollagen (COL) and osteopontin (OPN) mRNA expression was detected, primarily in the stromal cells, in malignant tumours compared with the benign tissue. The increased expression of the components of the uPA system on the epithelial tumour cells may account for the activation of the proteolytic cascade that occurs during breast cancer metastasis to bone. Furthermore, the over-expression of COL and OPN suggests a possible interaction between these matrix proteins and the uPA system.     

Topo2α protein expression predicts response to anthracycline combination neo-adjuvant chemotherapy in locally advanced primary breast cancer

Background:

This study aimed to identify predictors of response to anthracycline-based chemotherapy (5-fluoro-uracil, epirubicin, cyclophosphamide (FEC)) in locally advanced primary breast cancer (LAPC).

Methods:

A total of 91 LAPC patients were treated with six cycles of FEC before surgery. Protein expression of nine biomarkers (topoisomerase2α (Topo2α), ER, PR, HER2, Ki67, p53, EGFR, CK5/6 and CK14) was assessed in pre-chemotherapy core biopsies using immunohistochemistry (IHC) and results correlated with clinical and pathological response.

Results:

Clinical (cCR) and pathological (pCR) complete response were seen in 34.1% (n=31) and 20% (n=18), respectively. Pathological complete response was concordant with cCR in 14/31 cases; in four cases of cPR with palpable residual breast tumours, histology showed fibrous tissue only (pCR). On univariate analysis, pre-chemotherapy high expression of Topo2α protein (P=0.031), and negativity for ER and EGFR (P=0.001 and P=0.005, respectively) correlated with pCR. Positivity for p53 also showed significance (P=0.015), whereas basal phenotype, HER2, and all the clinicopathological variables of LAPC included in this study did not show significant correlation with response. On multivariate analysis, Topo2α expression had the strongest correlation with pCR (P=0.021) followed by EGFR (P=0.044).

Conclusion:

The study suggests that pre-chemotherapy Topo2α protein expression measured by IHC strongly correlates with pathological CR to neo-adjuvant anthracyclines in this group of LAPC studied.     

Gene expression in “young adult type” breast cancer: a retrospective analysis

Background: Young women with breast cancer experience inferior outcome and commonly manifest aggressive biological subtypes. Data is controversial regarding biological differences between breast tumors in young (diagnosed at <40 years of age) versus older women. We hypothesize there may be age-related expression differences in key genes for proliferation, invasion and metastasis within and across breast cancer subtypes, and that these differences correlate with outcome.Methods: Using clinically-annotated gene expression data from 778 breast tumors from three public databases, we compared clinico-pathologic characteristics, mRNA expression of 17 selected genes, and outcome, as a function of age (< 40 years vs. ≥ 40 years).Results: 14 of 17 genes were differentially expressed in tumors of young vs. older women, 4 of which persisted after correction for subtype and grade (p ≤0.05). BUB1, KRT5, and MYCN were overexpressed and CXCL2 underexpressed in young women. In multivariate analysis, overexpression of cytokeratin genes predicted inferior DFS only for young women. Overexpression of ANGPTL4 strongly predicted inferior DFS in basal but not HER2-enriched tumors in young women. Overexpression of cytokeratin genes and MYBL2 and low SNAI1 expression correlated with inferior DFS in HER2-enriched tumors in younger women. Kaplan-Meier analysis within the basal and HER2-enriched subgroups showed that overexpression of cytokeratin genes was associated with inferior DFS for young, but not older women.Conclusions: This preliminary study reveals age- and subtype-related differences in expression of key breast cancer genes for proliferation, invasion and metastasis, which correlate with prognostic differences in young women and suggest targeted therapies.     

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)

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?Ctaxane?Ctrastuzumab 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?C0.9), 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.