Discordance In HER2 Status Research Articles

PD05-05: Meta Analysis of Discordant HER2 Status in Matched Primary and Metastatic Breast Cancer.

Abstract Background: The status of HER2 amplification in breast cancer is an important prognostic and predictive indicator. Only those tumors exhibiting HER2 overamplification are candidates for HER2 targeted therapy. It remains controversial how accurately HER2 status of primary tumors reflects HER2 status in distant metastases. Discordance between primary and metastatic tumors can impact significantly on patient management and suitability for HER2 targeted therapies in the setting of recurrent distant disease. Methods: A literature search of the PubMed database was performed to identify all primary studies comparing HER2 status in matched primary and distant metastatic tumors between January 2005 and February 2011. Review and data extraction was performed by two independent reviewers. Eligible studies evaluated HER2 status by current ASCO guidelines. Studies comparing paired primary and axillary lymph nodes or synchronous primaries and metastases were excluded. Weighted pooled estimates were calculated. Results: The original search strategy retrieved 1703 studies for which there were 62 eligible studies for full evaluation. Metastatic sites included bone, brain, lung and liver. Traztuzumab was received in three studies. Weighted summary estimate for negative to positive discordance was 23% (95% CI, 16.0-28%). Positive to negative discordance had a weighted summary estimate of 4% (95% CI, 0.0-6%). Discussion: Meta analysis of studies adhering to ASCO guidelines for HER2 status determination revealed a significant rate of change to HER2 positive metastatic disease in HER2 unamplified primary breast cancers. This data suggests that nearly one quarter of patients may be denied the benefit of HER2 targeted therapy if HER2 primary status alone is used a the sole measure in determining therapeutic options upon distant recurrence. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD05-05.

Loss of Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Metastatic Sites of HER2-Overexpressing Primary Breast Tumors

We evaluated whether patients with human epidermal growth factor receptor 2 (HER2) -positive primary breast tumors had metastatic tumors that were HER2 positive (concordant) or HER2 negative (discordant). We then evaluated whether treatment with trastuzumab or chemotherapy before biopsy of the metastasis had any effect on the rate of HER2 discordance. We also compared the overall survival durations of patients with HER2-concordant and -discordant tumors. We retrospectively identified all patients who initially had been diagnosed with HER2-positive (immunohistochemistry 3+ and/or fluorescent in situ hybridization positive) primary breast cancer between 1997 and 2008 at MD Anderson Cancer Center who also had metastatic tumor biopsy results available for review. We included 182 patients who met our criteria. Forty-three (24%) of the 182 patients with HER2-positive primary tumors had HER2-negative metastatic tumors. The HER2 discordance rates differed significantly on the basis of whether patients received chemotherapy (P = .022) but not on the basis of whether patients received trastuzumab (P = .296). Patients with discordant HER2 status had shorter overall survival than did patients with concordant HER2 status (hazard ratio [HR], 0.43; P = .003). A survival difference remained among the 67 patients who received trastuzumab (HR, 0.56; P = .083) and 101 patients who did not (HR, 0.53; P = .033) before their metastasis biopsies. We confirmed that loss of HER2-positive status in metastatic tumors can occur in patients with primary HER2-positive breast cancer. Our data strongly support the need for biopsies of metastatic lesions to accurately determine patient prognosis and appropriate use of targeted therapy.

Abstract P6-05-02: Clinical-Pathological Features of All Nodules with the Same Histotype Affect Systemic Adjuvant Treatment Decision in Multifocal and Multicentric Breast Cancer

Abstract BACKGROUND Decision criteria about systemic adjuvant treatment of patients affected by breast cancer include estrogen receptor (ER), progesterone receptor (PgR), HER2 status, histologic grading, and proliferative index. In case of multifocal or multicentric breast cancer, the College of American Pathologists (CAP) recommends to provide features for the largest invasive carcinoma. We evaluated the discordance of ER, PgR, HER2, grading, and proliferative index among all nodules with the same histotype of patients with multifocal or multicentric breast cancer and the impact on the choice of adjuvant treatment. METHODS We retrospectively analyzed 113 consecutive patients operated for breast cancer between 2004 and 2009 in Forli (Italy). We performed histological examination of all nodules of each patient after surgery, at the same time. Immunohistochemical methods were used to detect ER/PgR status, and proliferative index (Ki67), whereas fluorescent in situ hybridization was used to determine HER2 status. ER/PgR < 10% was considered negative. Ki67 was considered high if ≥20%. Grading was determined according to Nottingham's score system. HER2 amplification was defined according to CAP guidelines or as the presence of a focal HER2 amplified clone ≥30% of tumor cells. We considered as “discordance” a difference in at least one nodule for any of the biologic features considered. In order to determine whether discordance among nodules affects systemic treatment approaches, we asked ten independent oncologists whether and how they would modify their prescribed adjuvant treatment. RESULTS Discordance in ER or PgR status among different nodules was detected in 5 (4.4%) and 16 patients (14.1%), respectively. The majority of the oncologists (7 out of 10) decided to modify their prescribed systemic treatment in 3 patients (2.6%), in favor of a combined treatment (endocrine plus chemotherapy), instead of endocrine-or chemotherapy alone as if their decision was based on the receptor status only of the largest nodule. Discordance in HER2 status was detected in 10 (8.8%) patients. In 4 patients (3.5%), all clinicians found indication to an anti-HER2 treatment. Discordance in proliferative index occurred in 17 (15.0%) patients and discordance in grading was detected in 18 (17.8% over 101) patients. Five of ten oncologists decided to modify their prescribed systemic treatment by adding chemotherapy to endocrine-therapy alone in 5 patients (4.4%) based on Ki67 value, whereas there was no change based on grade. DISCUSSION This study shows a discordance for all analyzed histological features among different nodules with the same histotype in multifocal and multicentric tumors. In a total of 8 patients (about 7%) this discordance affected the therapeutic decisions of oncologists, resulting in changes of the prescribed adjuvant systemic treatment, with respect to the prescriptions based on the clinicopathologic features only of the largest nodule. Therefore, we conclude that the analysis of all nodules in case of multifocality/multicentricity should be taken into consideration, in order to identify the best adjuvant treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-05-02.

Abstract P1-13-03: Is Bone Biopsy of Metastatic Sites Useful in Advanced Breast Cancer Management?

Abstract Background: Biopsies of metastatic sites are not recommended in clinical practice to evaluate changes in biological features in advanced breast cancer (ABC) women. We assessed discordance in expression levels for estrogen receptor (ER), progesterone receptor (PgR) and epidermal growth factor receptor 2 (HER2), between primary tumor and bone metastases and its clinical impact on patient management. Material and Methods: We retrospectively analyzed 109 ABC patients (pts) underwent computed tomography guided bone biopsy at the European Institute of Oncology in Milan, Italy, from 1997 to 2009. Data on ER and PgR status [positive if ≥1% by immunohistochemistry (IHC)] and on HER2 status (positive if IHC3+ and/or FISH amplified), both primary tumor and bone metastases were collected. Fisher and McNemar's test were used for statistical analysis. Results: Median time from primary diagnosis to bone biopsy was 4.2 years (range 0-18.9). Overall discordance rate (ODR) in ER expression was 20.5% (95% CI: 13.4%-29.5%): 3/7 pts (42.9%) shifted from ER negative to positive and 19/100 pts (19%) from ER positive to negative [p=0.0006]. ODR in PgR expression was 43.9% (95% CI: 34.3%-53.8%): 4/21 pts (19%) changed from PgR negative to positive and 43/86 pts (50%) from PgR positive to negative [P<0.0001]. ODR in HER2 status was 6.9% (95% CI: 2.6%-14.6%): 4/78 pts (5.1%) changed from HER2 negative to positive and 2/8 pts (25%) turned from HER2 positive to negative [p=0.41]. Thirteen out of 21 pts (61.9%) with discordant ER status and 23/77 pts (29.8%) with concordant ER status [p=0.01] changed endocrine therapy; there were no differences in chemotherapy [p=0.80]. Four out of 6 pts (66.6%) with discordant HER2 status and 6/72 pts (8.3%) with concordant HER2 status changed immunologic therapy [p=0.002], 3/6 pts (50%) started trastuzumab and 1/6 patient (16.6%) stopped it; there were no differences in chemotherapy [p=0.68]. All pts well tolerated the invasive procedure, requiring only local analgesia. Discussion: Our analysis showed that receptor profile may significantly change between primary breast cancer and bone metastases, with relevant impact on therapy. Bone biopsy might be useful and should be considered in selected cases to optimize therapeutic choices. Large prospective trials are needed to investigate these outcomes. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-03.

Molecular imaging of HER2-positive breast cancer: a step toward an individualized 'image and treat' strategy.

HER2 overexpression is correlated with aggressive tumor behavior and poor clinical outcome. Therefore, HER2 has become an important prognostic and predictive factor, as well as a target for molecular therapies. The article reviews recent advances in molecular imaging of HER2 that could facilitate individual approaches to targeted therapy of HER2-positive breast cancers. Because of the heterogeneity of breast cancer and possible discordance in HER2 status between primary tumors and distant metastases, assessment of HER2 expression by noninvasive imaging may become an important complement to immunohistochemistry or fluorescence in-situ hybridization analyses of biopsied tissue. Monoclonal antibodies such as trastuzumab and pertuzumab, or small scaffold proteins such as affibody molecules are used as HER2-targeting agents. For imaging purposes, these agents are labeled with positron or gamma-emitting radionuclides, optical dyes, or paramagnetic contrast molecules for positron emission tomography single photon emission tomography optical, and magnetic resonance imaging, respectively. HER2-specific molecular probes, combined with modern imaging techniques to provide information on HER2 expression not only in primary tumors but also in distant metastases not amenable to biopsy, may reduce problems with false negative results and, thereby, influence patient management by selecting patients that would benefit from HER2-targeted therapies. The new 'image and treat' strategy, involving assessment of target presence and distribution in an individual patient followed by optimized, target-specific drug delivery, may potentially improve efficacy of cancer treatment while reducing side effects.

Discordant HER2 Total and HER2 Homodimer Levels by HERmark Analysis in Matched Primary and Metastatic Breast Cancer FFPE Specimens.

Abstract Background: HER-2/neu is over-expressed in approximately 25% of primary invasive breast cancers and selection of patients for consideration of trastuzumab is a critical step in defining the treatment plan. We have previously reported that quantitative measurements of HER2 protein expression (H2T) and HER2 homodimers (H2D) using the HERmark assay identifies sub-populations of “HER2-positive” patients (by IHC and/or FISH) that have different clinical outcomes on trastuzumab (Leitzel, ASCO 2008; Lipton, SABCS 2008). Previous studies report up to a 20 % discordance in HER2 status using conventional IHC or FISH analysis between the primary and metastatic breast tumors. Here we correlate HER2 total and homodimer levels in matched primary and metastatic tissue from the same patient.Methods: 27 patients had matched primary and metastatic FFPE (formalin-fixed, paraffin-embedded) specimens tested in the HERmark assay to quantitate and compare their H2T and H2D expression levels.Results: FFPE tissue was available from 27 primary breast cancers and metachronous metastatic sites. Metastatic lesions included 7 skin, 5 lymph node, 3 bone, 3 pleura, 2 brain, 2 chest wall, and 5 other soft tissue lesions. The median elapsed time between matched primary and metastatic sites was 71 mo. (range 9-137 mo). During the time period between the primary specimen harvest and the metastatic biopsy, 6 patients were treated with chemotherapy alone, 10 received hormonal therapy without trastuzumab, 3 patients received trastuzumab, and 3 received no treatment. Treatment was not known for 5 patients. For the whole population, there was a weak to moderate positive correlation between primary and metastatic cancers with H2T (r2=0.36, p<0.001) and for H2D (r2=0.27, p<0.006). Using the optimized time to progression (TTP) positional scanning cutpoints for H2T and H2D defined in our previous reports, 4/20 patients (20%) converted from low to high, and 1/7 (14%) converted from high to low H2T. Using the H2D cutpoint, 7/15 patients (47%) converted from low to high, and 3/12 (25%) converted from high to low H2D. Overall discordance between primary and metastatic sites was 19% for H2T, and 37% for H2D.Conclusions: HERmark analysis of matching primary and metastatic breast cancers revealed 19% discordance for H2T, and 37% for H2D. The most frequent conversion was from low HER2 in the primary tissue to high HER2 in the metastatic site. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2131.

HER2 Discordance between Primary Breast Carcinoma and Locoregional or Distant Metastatic Disease in Pts Treated in a Single Institution.

Abstract Background Published data quotes HER2 status discordance rates between primary breast cancer and subsequent metastases of 0-38%. Studies employing immunohistochemistry (IHC) have generally found higher discordance rates than those employing in situ hybridization (ISH), suggesting methodological issues may play an important role in apparent discordance. It has also been proposed that the rate of discordance is higher in metachronous distant metastases than in synchronous or locoregional metastases. This study aims to assess the incidence of true HER2 status discordance between primary and loco-regional or metastatic breast cancer in a cohort of patients (pts) sourced from a single institution, with HER2 ISH-testing from a single reference laboratory with uniform methodology. A secondary aim is to determine the role that intratumoural heterogeneity plays in discordant HER2 status.Method Data collected prospectively for all breast cancer pts treated over the preceding 10 years were reviewed to identify pts with subsequent locoregional or metastatic recurrence where tissue was available from both primary and recurrent lesions. Patient consent was obtained for testing of previously untested samples. HER2 IHC had been previously performed using a variety of assays at local laboratories in 116 paired samples; the remaining samples were centrally tested using DakoA0485 antibody on Ventana XT autostainer. HER2 gene copy was assessed by Ventana INFORM HER2/ch17 SISH probes, with Vysis PathVysion HER2/cep17 dual colour FISH probe employed in cases which were equivocal/non diagnostic by SISH.Results Between 3/1999 and 6/2009, 450 with metastatic breast cancer and 45 pts with local recurrence only were seen. 204 pts (41%) underwent biopsy of the recurrence, where 16 pts had insufficient tissue for analysis in this study. Of the remaining 188 pts, 168 had metachronous recurrent disease (151 metastatic, 37 locoregional) and 20 synchronous metastatic disease, At diagnosis, pts were stage I (22%), II (40%), III (24%), IV (11%), unknown (3%); with mean age 54yrs (range 31-94). Biopsy of recurrence was from breast (20%), Lymph node (19%), Bone (12%), Chest wall (8%), Skin (7%), Liver (7%), Lung (7%), Brain (7%), Other (6%), Pleura (5%), Soft tissue (2%). HER2 IHC testing by local laboratories (116 paired samples) had shown complete concordance between primary and recurrence in only 50 pts (43%). HER2 status in the primary was negative or equivocal (i.e. 0, 1+ or 2+) with conversion to HER2 3+ in the recurrence in 8 pts (6.9%) and the converse in 10 pts (8.6%), resulting in an IHC discordance rate of 15.5%.All tumour samples will be centrally reviewed by ISH to assess for the true rate of discordance between the paired samples. An exploratory analysis of the effect of discordance on response to first-line metastatic treatment and breast cancer outcome will be made.This study was supported by a grant from Roche Australia Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2024.

HER‐2 status discrepancy between primary breast cancer and metastatic sites. Impact on target therapy

In this prospective study, we determined HER-2 status in primary breast invasive carcinomas and in the paired lymph node metastases (synchronous and metachronous), local recurrence and metachronous distant metastases, to verify the percentage of discordant cases. HercepTest and Fluorescence in situ hybridization (FISH) were used to determine HER-2 status on 119 cases of primary infiltrating breast carcinoma and paired metastases (45 cases with synchronous lymph node metastases, 9 cases with metachronous lymph node metastases, 30 cases with local recurrence, and 35 cases with metachronous distant metastases). A therapeutically significant HER-2 status discordance was demonstrated between primary carcinoma and synchronous lymph node metastases (6.7%), local recurrence (13.3%) and metachronous distant metastases (28.6%). In the first comparison, there was a normal HER-2 status in primary tumours and HER-2 amplification in paired metastases, in the second the opposite phenomenon was present, and both types of discordance were evident in the third comparison. Considering the cases of local recurrences and metachronous distant metastases all together, 14 out of 65 cases (21.5%) showed a therapeutically significant discordance of HER-2 status between the primary tumour and the paired metachronous recurrence or metastasis (p < 0.001), the 15.4% of cases showing normal HER-2 status in the primary tumour and HER-2 amplification in the neoplastic relapse. For the treatment of metastatic patients, the evaluation of HER-2 status should be performed in neoplastic tissue from metastatic site, whenever possible. This procedure could be also suggested in the patients that are metastatic at the time of diagnosis.