HER2 discordance between primary and metastatic breast cancer: Assessing the clinical impact

Background

In the setting of breast cancer relapse, treatment decisions are typically made by utilizing HER2, estrogen, and progesterone receptor expression status of the primary breast cancer. Recently, concern regarding receptor discordance has led to recommendations for rebiopsy for all cases of metastatic disease. However, whether this is an appropriate recommendation is uncertain, particularly as the clinical implications for HER2 discordance are unknown.

Methods

We performed a literature review to identify studies assessing HER2 discordance between primary and metastatic breast cancer. These studies were then reviewed for data relating to (1) impact of clinical factors on discordance rates, (2) prognostic impact of discordance, or (3) clinical outcomes from treatment alteration due to receptor discordance. Results were analyzed qualitatively.

Results

From 60 HER2 discordance studies identified, 24 contained information of interest for this review. No clear factor promoting HER2 discordance was identified. Loss of HER2 seemed to result in worse post-relapse survival and overall survival, although these data were often confounded by lack of treatment in the setting of receptor loss. Conversely, HER2 discordance was not associated with shorter DFS. Individual patients with receptor gain appear to have benefited from addition of targeted treatment, although data are limited to case reports.

Conclusion

Evidence of HER2 discordance leading to alterations in patient outcomes is limited, highlighting the need for further research in this area. Furthermore, lack of alteration in patient outcomes suggests that a more pragmatic approach to the decision to rebiopsy may be appropriate.     

Estrogen and HER-2 receptor discordance between primary breast cancer and metastasis

Discordance in estrogen receptor and human epidermal growth factor receptor 2 receptor status between the primary tumor and recurrence is frequently reported in the literature. This is frequently interpreted as evidence for a change in the biology of breast cancer during the course of the disease. This commentary discusses some of the caveats of this interpretation. Discordant receptor results can be caused by any of 3 factors: (a) a genuine switch in the biology of the disease, (b) sampling error in focally receptor-positive cancers, and (c) limited accuracy and reproducibility of receptor assays. The relative contribution of each of these factors to discordant results is unknown. A switch in molecular class between primary and recurrent cancer (or residual cancer after therapy) appears to be a rare event based on the available limited molecular profiling data. Small pockets of strongly focally receptor-positive tumor nests in a larger receptor-negative cancer are also relatively infrequently seen. Discordance resulting from inherent limitations in assay reproducibility is evident from the frequently discordant receptor results even when the same samples are assessed in different laboratories (e.g., central versus local laboratory). A repeat tumor biopsy is clearly justified when it is suspected, on clinical grounds, that the original receptor results may have been false negative or when the diagnosis of metastatic disease is in question. However, routine repeat biopsy for receptor re-evaluation does not necessarily improve diagnostic accuracy and have a potential to harm through a false-negative result. For patients with clinical courses consistent with hormone responsiveness, or with prior positive hormone receptor results, a course of endocrine therapy is reasonable regardless of the most recent hormone receptor assay result.     

Prognostic impact of early detection of contralateral primary breast cancer

The authors report on a consecutive series of 175 contralateral metachronous breast cancers. Eighty-six cases detected in women self referring for cancer-related subjective symptoms were compared to 89 cases detected as asymptomatic at routine examination. Detection in the asymptomatic phase was associated with a more favorable stage, but no differences in survival rates were observed between asymptomatic or symptomatic cancers when survival was measured from the date of first cancer diagnosis, in order to adjust for lead time bias. The nodal status of the first or of the second cancer was the only variable of prognostic value on univariate analysis, whereas a significant association to prognosis was evidenced only for nodal status of the first cancer. The study suggests that routine clinico-mammographic check-up may achieve early detection of contralateral metachronous breast cancer in the asymptomatic phase, but this does not seem to have a relevant impact on prognosis. The occurrence of a second primary breast cancer seems to be an indicator rather than a determinant of a worse prognosis.     

Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer

Introduction

We have previously reported that tumour-specific expression of the rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR), in the mevalonate pathway is associated with more favourable tumour parameters in breast cancer. In the present study, we examined the prognostic value of HMG-CoAR expression in a large cohort of primary breast cancer patients with long-term follow up.

Methods

The expression of HMG-CoAR was assessed by immunohistochemistry on tissue microarrays with tumour specimens from 498 consecutive cases of breast cancer with a median follow-up of 128 months. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the rate of recurrence-free survival (RFS) and breast cancer specific survival (BCSS).

Results

In line with our previous findings, tumour-specific HMG-CoAR expression was associated with low grade (p < 0.001), small size (p = 0.007), oestrogen receptor (ER) positive (p = 0.01), low Ki-67 (p = 0.02) tumours. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS, even when adjusted for established prognostic factors (relative risk [RR] = 0.60, 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In ER-negative tumours, however, there was a trend, that was not significantly significant, towards a shorter RFS in HMG-CoAR expressing tumours.

Conclusions

HMG-CoAR expression is an independent predictor of a prolonged RFS in primary breast cancer. This may, however, not be true for ER-negative tumours. Further studies are needed to shed light on the value of HMG-CoAR expression as a surrogate marker of response to statin treatment, especially with respect to hormone receptor status.     

Prognostic factors in primary breast cancer

A review and update of published studies on oestrogen receptor and progesterone receptor as prognostic factors in breast cancer supports the following conclusions. In stage I breast cancer the lack of oestrogen receptor seems to be the most important factor for predicting earlier recurrence and poorer survival. In stage II breast cancer, measurement of progesterone receptor appears to be better than measurement of oestrogen receptor for predicting disease-free survival, and is as important as the oestrogen receptor in predicting overall survival. The benefits of adjuvant endocrine therapy are better predicted by the presence or absence of progesterone receptor rather than by oestrogen receptor. Measurement of proliferative activity (DNA S-phase) by thymidine labelling or flow cytometry, and of aneuploidy by flow cytometry, also provides prognostic information. The strong correlations between tumour receptor content, per cent S-phase and aneuploidy suggest that these measurements in concert might identify a subset of stage I breast cancer patients at increased risk for recurrence, who would thus be potential candidates for adjuvant therapy.     

Incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases

ER, PgR and HER-2 status are the cornerstones of choosing systemic therapy for breast cancer, but can change during the disease course. Guidelines recommended the biopsy of the metastatic tumor to reassess receptor status. Bone is the most frequent metastatic site of breast cancer but remained technically difficult to biopsy. Our study aimed to evaluate the incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases. One hundred and fifty-five breast cancer patients were diagnosed with pathology-confirmed bone metastasis at Fudan University Shanghai Cancer Center. Ninety-three patients with receptor status available on both primary tumor and bone metastases were included in our study. ER, PgR and HER-2 status converted from positive to negative in 10.8% (10/93), 28.0% (26/93) and 8.6% (8/93) of the patients, while ER, PgR and HER-2 status converted from negative to positive in 3.2% (3/93), 4.3% (4/93) and 1.1% (1/93) of the patients, respectively. 40.4% (17/42) of the HER2-0 tumors converted to HER2-low, which enabled them to receive the treatment of new antibody-drug conjugates (ADCs). Prior endocrine and anti-HER2 therapy were the independent risk factors for receptor conversion. Loss of HR expression in bone metastases was significantly associated with worse first-line PFS (adjusted hazard ratio = 3.271, P-value = .039) and OS (adjusted hazard ratio = 6.09, P-value = .011). In conclusion, our study confirmed that patients may experience receptor conversion between primary breast cancer and bone metastases, possibly influenced by prior treatments, which significantly influenced prognosis. The rebiopsy of bone metastases in patients with primary HER2-0 tumors may benefit from the new ADC drugs.     

Prognostic impact of phosphorylated HER-2 in HER-2+ primary breast cancer

Purpose.

Tyrosine 1248 is one of the autophosphorylation sites of human epidermal growth factor receptor (HER)-2. We determined the prognostic value of the expression level of tyrosine 1248–phosphorylated HER-2 (pHER-2) in patients with HER-2⁺ primary breast cancer using a reverse-phase protein array.

Patients and Methods.

The optimal cutoff value of pHER-2 for segregating disease-free survival (DFS) was determined by receiver operating characteristic (ROC) curve analysis. Five-year DFS for pHER-2 expression level was estimated with the Kaplan-Meier method using both derivation (n = 162) and validation (n = 227) cohorts.

Results.

Of the 162 patients in the derivation cohort, 26 had high HER-2 expression levels. The area under the ROC curve for pHER-2 level and DFS was 0.662. Nineteen of the 162 patients (11.7%) had high pHER-2 expression levels (pHER-2^high); 143 patients (88.3%) had low pHER-2 expression levels (pHER-2^low). Among the 26 patients with high HER-2 expression levels, the 17 pHER-2^high patients had a significantly lower 5-year DFS rate than the nine pHER-2^low patients (23.5% versus 77.8%). On multivariate analysis, only pHER-2^high independently predicted DFS in the Cox proportional hazards model. In the validation cohort, among 61 patients with high HER-2 expression, the difference in 5-year DFS rates between pHER-2^high (n = 7) and pHER-2^low (n = 54) patients was marginal (57.1% versus 81.5%).

Conclusion.

In patients with HER-2⁺ primary breast cancer, pHER-2^high patients had a lower 5-year DFS rate than pHER-2^low patients. Quantification of pHER-2 expression level may provide prognostic information beyond the current standard HER-2 status.     

Heterogeneous gene alterations in primary breast cancer contribute to discordance between primary and asynchronous metastatic/recurrent sites: HER2 gene amplification and p53 mutation

The aim of the present study was to clarify differences in genetic events between primary breast cancers and asynchronous metastatic/recurrent lesions, by examining HER2 gene amplification and p53 mutation. The subjects were 44 breast cancer patients with asynchronous metastasis or recurrence. Synchronous metastases were excluded. HER2 overexpression and gene amplification were examined using immunohistochemistry and fluorescent in situ hybridization (FISH). P53 point mutation was examined by immunohistochemistry, laser-captured microdissection, PCR-single-strand conformation polymorphism, and a direct sequencing method. Immunohistochemistry showed that, for HER2, p53, ER and PgR, discordance rates between primary and recurrent tumor were 2 (4.5%), 1 (2.3%), 7 (15.9%) and 10 (22.7%), respectively. Two primary tumors with discordant HER2 overexpression were composed of at least two populations of carcinoma cells, with and without HER2 gene amplification. Distribution of HER2 gene amplification was consistent with protein overexpression. Corresponding recurrent tumors consisted of carcinoma cells without HER2 gene amplification. Of 6 recurrent tumors in which the primary carcinoma had a p53 point mutation, 3 tumors had identical mutations, 1 tumor had a different point mutation, and 2 tumors had no mutation. It was suspected that the latter 3 recurrent tumors comprised a minor component of the primary tumor. In the present study, we examined a large series of asynchronous recurrent tumors. A limited number of these tumors showed discordance between primary and recurrent tumors. Detailed observations revealed that cell populations present in recurrent tumors were also present in the primary tumors, although they comprised a minor component of the primary tumor. Heterogeneity of the primary tumor apparently contributed to discordance.     

Discordance in receptor status between primary and recurrent breast cancer has a prognostic impact: a single-Institution analysis

BackgroundTumor phenotype may change during breast cancer progression. This study evaluates the prognostic impact of receptor discordance between paired primaries and recurrences.Patients and methodsOne hundred and thirty-nine patients underwent histological sampling of suspected breast cancer recurrence. All the pathology assessments [ER, PgR and human epidermal growth factor receptor 2 (HER2)] on both primaries and confirmed recurrences were performed at the same laboratory.ResultsA breast cancer recurrence was confirmed in 119 cases. Rates of discordance were 13.4%, 39% and 11.8% for ER, PgR and HER2, respectively. Ninety-two patients maintained the same tumor phenotype [i.e. the same hormone receptors (HR) and HER2 status], whereas 27 (22.7%) changed during progression. The loss of HR positivity and the loss of HER2 positivity resulted in a worse post-recurrence survival (P = 0.01 and P = 0.008, respectively) and overall survival (OS; P = 0.06 and P = 0.0002, respectively), compared with the corresponding concordant-positive cases. Tumor phenotype discordance was associated with worse post-recurrence and OS (P = 0.006 and P = 0.002, respectively); those cases who turned into triple-negative experienced the poorest outcome, respect to the concordant group (P = 0.001, OS).ConclusionsWe demonstrated for the first time an impact on OS of phenotype discordance between primary breast cancer and relapse. Among discordant cases, receptor loss resulted in the main determinant of poorer outcome.     

原发性双侧乳腺癌的预后分析

目的分析影响双侧乳腺癌患者生存率的预后因素.方法对18例经病理组织学证实的原发性双侧乳腺癌患者进行回顾性分析.其中同时发生3例(16.7%);先后发生15例(83.3%),均接受手术、放疗、化疗等综合治疗.分析原发性肿瘤临床T分期、腋下淋巴结的转移、月经情况及两侧乳腺癌发生的间隔时间与患者生存率的关系.结果原发性肿瘤临床T分期、腋下淋巴结的转移及两侧乳腺癌发生的间隔时间为患者的主要预后因素.结论原发性双侧乳腺癌患者的原发灶大小、淋巴结浸润及两侧癌发生的间隔时间与患者的预后有显著关系;第二原发乳腺癌患者的早期发现,早期治疗可提高生存率.     

Prognostic impact of cyclooxygenase-2 in breast cancer

Cyclooxygenase (COX)-2, an inducible isoform of cyclooxygenases, regulates the rapid production of high levels of prostaglandins during inflammation. Cyclooxygenase-2 is overexpressed in a variety of malignant tumors. This review discusses epidemiologic and preclinical data on the role of COX-2 in the development and progression of breast cancer, and it will focus on recent studies that investigate the prognostic role of COX-2 in breast cancer. In rodent tumor models it has been shown that treatment with COX-1 or COX-2 inhibitors reduces incidence and growth of breast carcinomas. Possible mechanisms include regulation of invasion, increased proliferation, and suppression of apoptosis by COX-2. Moreover, there may be an indirect effect of prostaglandins, for example in tumor host interactions such as induction of stromal aromatase activity or enhancement of angiogenesis in tumor tissue. At least 8 different immunohistochemical studies have investigated expression of COX-2 in a total of 2392 primary breast carcinomas, of which 40% were found to be COX-2 positive. Overexpression of COX-2 is associated with indicators of poor prognosis, such as lymph node metastasis, poor differentiation, and large tumor size. Four studies have found that overexpression of COX-2 is linked to poor prognosis in breast cancer. These investigations provide the basis for further evaluation of a possible therapeutic effect of COX inhibitors in therapy of breast cancer.     

Prognostic impact of haemoglobin levels in breast cancer

BACKGROUND: Many patients with solid tumours suffer from anaemia, as a consequence of the disease itself or its treatment. Anaemia affects the quality of life and can have a negative impact on overall survival. The aim of the current study was to analyse the impact of haemoglobin levels on the prognosis of patients with primary breast cancer. PATIENTS AND METHODS: Retrospective data from 249 women treated for operable breast tumours were included in our study. Haemoglobin (Hb) levels independently of anticancer therapy were compared for the prognostic influence on disease-free and overall survival. RESULTS: A significant correlation between higher minimum Hb level during chemotherapy and the disease-free and overall survival was found. Pre-treatment haemoglobin levels had no prognostic influence on the disease-free and overall survival. CONCLUSION: The present data showed that anaemia during adjuvant chemotherapy to be a negative prognostic indicator for survival of patients with breast cancer.     

乳腺癌患者原发灶与复发转移灶中ER、PR、HER-2及Ki-67表达异质性的回顾性分析

目的:探讨ER、PR、HER-2及Ki-67在乳腺癌患者原发灶及复发转移灶中的表达差异,并分析其对乳腺癌患者预后的影响。方法:统计2012年01月01日2021年12月31日我院肿瘤科收治的复发转移性乳腺癌患者,除外病理及临床资料缺失的患者后,共计89例患者纳入本研究。采用回顾性队列研究方法,比较乳腺癌原发灶及复发转移灶中ER、PR、HER-2及Ki-67的表达差异。结果:本研究纳入患者的平均年龄为53.14岁(20~84岁)。其中有34例患者接受术前新辅助治疗,所有患者均行乳腺癌根治术或改良根治术,并进行了相应的术后辅助治疗。乳腺癌原发灶中ER及PR阳性表达率均高于转移灶;而HER-2阳性及Ki-67高表达的情况在转移灶中更常见。乳腺癌原发灶与复发转移灶中ER、PR、HER-2、Ki-67表达差异比例分别为:24.72%、42.70%、11.24%、13.48%。乳腺癌原发灶及转移灶中ER、PR表达的异质性与患者无病生存期相关。结论:乳腺癌患者的ER、PR、HER-2和Ki-67表达状态在原发灶与复发转移灶中存在一定的异质性,进而影响患者的治疗策略及预后。     

The discordance between primary breast cancer lesions and pulmonary metastatic lesions in expression of aldehyde dehydrogenase 1-positive cancer cells

Background

We evaluated the expression of aldehyde dehydrogenase 1 (ALDH1) between primary breast lesions and pulmonary metastatic (PM) lesions in breast cancer patients.

Methods

We retrospectively analyzed the clinicopathological features and the expression statuses of ER, PR, HER2, Ki-67 and ALDH-1 in both primary and metastatic breast cancer lesions and evaluated the discordance rates in the expressions of these markers between the primary and metastatic lesions, and also the prognostic value of these factors.

Results

None of the PM patients had metastases at any other sites, and all had undergone curative breast cancer surgery. The pulmonary operation was partial resection in 15 (88 %) patients and lobectomy in 2 (12 %) patients. The median overall survival (OS) after resection of the PNs (OS) was 48 months. The discordance rates in the expressions of ER, PR, HER2, Ki67 and ALDH-1 between the primary and metastatic lesions were 0, 29, 21, 43 and 50 %, respectively.

Conclusion

There was significant discordance in the biomarkers between the primary tumors and the metastatic lesions.     

Prognostic significance of serum IgE levels in primary breast cancer

Summary Serum IgE was measured in presurgical sera from 166 nonallergic women admitted to a comprehensive, multidisciplinary study of primary, operable breast cancer. During the follow-up period, which averaged 48 months, there were 71 recurrences. Patients were divided into two groups: those with IgE levels greater than the geometric mean value of 24 I.U. and those with levels less than the mean. The rate of tumor recurrence was significantly greater for the IgE > 24 group (p<0.03). IgE remained a significant prognostic indicator when evaluated by Cox regression analysis in conjunction with other known prognostic factors including: number of positive lymph nodes, clinical stage, menopausal status, estrogen receptor status, mitotic grade, tumor diameter, breast feeding history, and age of patient (p<0.015). IgE was not correlated with any of these known prognostic factors in individual analyses. We conclude that serum IgE level is a significant, independent prognostic indicator in primary breast cancer. Address for reprints: Dr H. Ownby, Michigan Cancer Foundation, 110 East Warren Avenue, Detroit, MI 48201, USA.