Changes in biologic features between primary and recurrent or relapsed breast cancers

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1 Changes in biologic features between primary and recurrent or relapsed breast cancers S. Al-Awadi, S. Thuruthel, K. Yamini, P. Muraligopal, I. Maarouf, A. Atta Department of Medical Oncology, Kuwait Cancer Control Centre, Kuwait Abstract Objective: Changes in ER, PR and Her2 receptor status between primary and metastatic cancer tissue have been suggested in breast cancer. The frequencies of these changes are still not fully understood. The purpose of this study was to evaluate these changes in breast cancer population of Kuwait. Subjects and Method: Changes in the biological features between primary and recurrent disease in 70 patients who presented between 2009 and 2012 was studied. Statistical comparisons between groups was done using chi square test while Kaplan Meier method was used to perform analysis of survival after relapse. All analysis was carried out using the IBM-SPSS statistical software. Results: There was a decrease in ER and PR positivity from 61.4% to 58.6% and 61.4% to 44.3% respectively. The overall change in ER and PR status was 28.5% and 25.7% respectively. There was an increase in the Her2 positivity as the tumor relapsed and overall changes were seen in 5.7% of cases. Conclusion: Patients with breast cancer experience change in biological markers through the course of their disease. The changes are more with hormone receptors compared to Her2. Re-biopsy should be considered at relapse if feasible. Keywords: breast cancer, hormone receptors, Her2 neu, receptors, biological features, changes Introduction Determination of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2) has become an integral part of the treatment paradigm of breast cancer (1). These markers have helped us in classifying breast cancer into various subtypes as well as in prognosticating and determining therapeutic options (2). In the adjuvant setting, it is important in the determination for the need of chemotherapy, hormonal and Her2 targeted therapy with Trastuzumab. In metastatic disease, these biological markers along with disease free survival and sites of recurrence help us choose the various treatment options (3, 4). Corresponding Author: Dr. Sanjay Thuruthel, Department of Medical Oncology, Kuwait Cancer Control Centre, P.O. Box 42262, Shuwaikh 70653, Kuwait. Tel. No , sthuruthel@hotmail.com 19 It has been shown that these markers can vary in initial resected primary tumor as well as in metastatic tumor (5-7). Although treatment of recurrent disease is based on ER, PR and Her2neu status, re-biopsy of lesions has not become a required standard of care. NCCN recommends biopsy of lesions whenever feasible (4). The biological change is mainly in the hormonal receptors while few changes are seen in the Her2neu receptors. A few studies have been published showing changes even in the Her2neu positivity. The discordances in the various studies are in the range of 0-34 % (8-11). It has been hypothesized that differences in primary tumor and metastatic tumor could be a result of genetic drift during progression or intra tumoral heterogeneity wherein the clone with more aggressive phenotype starts micro metastatic process from the beginning (12,13). It also has been proposed that treatment might also

2 Changes in biology of breast cancer on relapse, Sanjay Thuruthel, et. al. interfere with the results by selecting resistant clones. But there is controversy regarding whether the physician will change the treatment depending on the results and whether it will affect the overall prognosis of patients (14, 15). The aim of this study was to collect data regarding change in biological features between primary and recurrent breast cancer from the same patients of the Kuwait population. Patients and methods Kuwait Cancer Control Centre [KCCC] is the only comprehensive oncology centre catering to the population of Kuwait. All breast cancer patients presenting with relapse or recurrent disease and attending the centre between June 2009 and June 2012 were counseled for rebiopsy from the recurrent/metastatic site. ER and PR status were assessed by IHC studies with a threshold of 10% or more to be classified as positive. Her 2 was initially assessed by IHC and a score 3+ was taken as positive. Patients with an equivocal IHC score of 2+ had FISH done with a threshold her2neu/cep17 ratio 2 taken as positive or amplified. These results were then compared with the retrospective data available in the registry of the ER, PR and Her2 status of the primary tumor for these patients. The patients were classified as: Hormone Receptor (HR) positive and Her2 negative tumors were classified as luminal A type, HR and Her2 positive tumors as luminal B type, HR negative and Her2 positive as Her2 type, and HR and Her2 negative as Triple negative (TN) type. Statistical comparison between groups was done using chi square test while Kaplan-Meier method was used to perform analysis of survival after relapse according to biological marker change. The log-rank statistic was used for univariate comparisons of survival end points. For univariate and multivariate comparisons, a logistic regression model was used. All analyses were carried out using the IBM-SPSS statistical software. The median time period of observation after recurrence was 13 months. The baseline characteristics of all the patients with recurrent breast cancer enrolled in this study is presented in (Table 1). 20 Seventy patients had the pathology verification for both primary and recurrent tumor. The median age was 51years. 85.7% of patients had tumor greater than 2 centimeters while 22.9% had node negative disease. 61.4% had ER and PR positive disease initially while 27.1% were Her2 positive. Table 1: Characteristics of all patients with recurrent breast cancer in this study [n=70]

3 42.9% had disease free interval (DFI) of 2-5 years while 37.1% had > 5 years. The common sites of biopsy were chest wall (34.3%) and liver (14.2%). G. J. O. Issue 15, 2014 in ER, PR and Her2 occurred in patients having DFI greater than 2 years. Changes in subtype of tumor are shown in (Table 5). The discordance rate was maximum for Luminal B subtype. Results The changes in biological marker status between primary and matched recurrent tumors are shown in Table 2-5. The overall change in positivity for ER was 61.4% to 58.6%, for PR it was 61.4% to 44.3%, and for Her2 it was 27.1% to 30% in the recurrent tumor when compared to the primary tumor. Changing from hormone positive to negative was common for both ER and PR. PR showed more patients becoming negative than positive compared to ER. More patients had Her2nue positive tumor at relapse compared to primary tumor. Category changes for each biological marker and correlation with DFI is shown in (Table 4). The biggest change Table 2: Changes in positivity rates of biological markers between primary and relapsed/recurrent tumor Table 3: Changes in biological marker status between primary breast tumor and relapsed/recurrent tumor Table 4: Changes in biological marker status between primary breast tumor and recurrent tumor based on DFI p value = NS for all parameters Table 5: Changes in breast cancer subtype between primary breast tumors and matched recurrent lesions. p value = <

4 Changes in biology of breast cancer on relapse, Sanjay Thuruthel, et. al. Discussion Discordances in the biological markers between primary and recurrent breast cancer has been documented by several studies. Most published data are from the western world. In our study we present a data on 70 patients from Kuwait. Although our centre caters to the whole population of Kuwait and is the only centre offering oncology services, our study limitation was the difficulty in getting consent for a re-biopsy from breast cancer patients. Data on a large cohort of patients over a period of 10 years was recently described from Stockholm Health care region by Lindstrom et al and also presented at ASCO 2010 showing the instability of ER, PR and Her2 (16). Nishimura et. al. have also published a recent report from Japan on the changing biological markers during relapse (17). The changes in hormone receptors are more frequent than the Her2 changes. In our study, there was a decrease in ER and PR positivity from 61.4% to 58.6% and 61.4% to 44.3% respectively. The overall change in ER and PR status was 28.5% and 25.7% respectively. In the Stockholm study, one in 3 patients experienced an alteration of hormone receptor status at relapse. In the study of Nishimura et. al. there was a decrease in ER positivity from 63.5% to 57.7% and PR from 56.7% to 43.3%. Of note is a larger alteration in PR positivity status at relapse when compared to ER. These results correlate with many study results. Some studies using multivariate analysis have hypothesized that PR positivity changes may be the first change occurring at relapse may indicate poor overall survival. Her2 changes based on various studies have varied values from 0-35%. In our study, there was an increase in the Her2 positivity as the tumor relapsed and overall changes were seen in 5.7% of cases. The largest report on Her2 changes showed discordance in 33.2% with 23.6% changing from positive to negative and 9.6% changing from negative to positive (18). Most changes in the biological markers were seen in patients with a disease free interval (DFI) of > 2 years and the maximum changes were seen Fig. 1 : Survival analysis according to biological marker change. [ p value=0.72] in HR in the patients who relapsed after 5 years, however statistically not significant. Of note is that most patients whose ER changed positive to negative were on hormonal treatment. A study by Guarnaeri et. al. have shown the same results with virtually all of their patients who turned HR negative with relapse having received hormonal therapy and they have hypothesized that this might be due to acquired hormonal resistance (19). An interesting analysis done by Nishimura et. al. is the change in breast cancer subtypes. The discordance rates for Luminal A and B were high at 28.8% and 33.3% respectively while it was low for triple negative and Her2 subtypes. Our study also shows the same where the highest discordance was seen in the Luminal B subtype. The implication on prognosis due to these changes has been studied by some reports. In the study by Lindstrom et. al., patients with ER status that changed from positive to negative had a statistically significant increased hazard ratio for death. However, in our study there was no change in survival with biological marker difference or pathological type change, probably because of short follow-up and less number of events. (Figure 1) 22

5 G. J. O. Issue 15, 2014 There are several limitations of this study. This is a retrospective study and therefore the analysis carries the pitfalls inherent to most retrospective reviews. This was a chart review with the receptor status being typically taken from the pathology report. Some patients have their primary tumor and metastatic tumor tested at different pathology laboratories. There was no central pathology review. This analysis is therefore subject to inter laboratory variations. Secondly, for both hormone receptor and her2 receptor analysis there were often different assay methods used in the primary and metastatic specimens and these could have confounded the results. Despite these limitations, this study with a small number of patients shows that significant receptor discordance occurs between primary and metastatic tumor in breast cancer. Conclusion Patients with breast cancer experience unstable biological markers through the course of their natural history. The changes are more with HR compared to Her2. These changes in biological characteristics may influence treatment decisions taken at relapse and rebiopsy should be considered whenever feasible. References 1. Hortobagyi GN : Treatment of breast cancer. N Engl J Med : Adedayo A, Onitilo, Jessica M, Rober T, Bickol NM: Breast Cancer Subtypes Based on ER/PR and Her2 Expression, Comparison of Clinicopathologic Features and Survival. Clinical Medicine & Research 2009; Volume 7, Number 1/2: Goldhirsch A,Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ, Panel members: Thresholds for therapies, highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer Ann Oncol 2009; 20(8): NCCN Clinical Practice Guidelines in Oncology. Breast Cancer; Version 2; Broom RJ, Tang P, Simmons C et al: Changes in estrogen receptor (ER), progesterone receptor (PR) and HER2 status with time: Discordance rates between primary and metastatic breast pathology samples. Anti cancer research 2009; 29(5): Aitken SJ, Thomas JS, Langdon SP, Harrison DJ, Faratian D: Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal Metastases. Ann Onco 2010; 21: Holdaway IM, Bowditch JV: Variation in receptor status between primary and metastatic breast cancer. Cancer 1983; 52: Gancberg D, Di Leo A, Cardoso F, Rouas G, Pedrocchi M, Paesmans M, Verhest A, Bernard-Marty C, Piccart MJ, Larsimont D: Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. Ann Oncol 2002; 13: Sari E, Guler G, Hayran M, Gullu I, Altundag K, Ozisik Y: Comparative study of the immunohistochemical detection of hormone receptor status and HER-2 expression in primary and paired recurrent/metastatic lesions of patients with breast cancer. Med Oncol 2011; 28(1): Zidan J, Dashkovsky I, Stayerman C Basher W, Cozocov C, Hadary A: Comparison of HER-2 over expression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease. Br J Cancer 2005; 93: Gong Y, Booser DJ, Sneige N: Comparison of HER-2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma. Cancer 2005; 103: Edgerton SM, Moore D 2nd, Merkel D et al: erbb- 2 (HER-2) and breast cancer progression. Appl Immunohistochem Mol Morphol 2003; 11: Pertschuk LP, Axiotis CA, Feldman JG Constantine A, Joseph GF, Yong DK, Sebastian J, Karavattayhayyil, Lorraine B: Marked intratumoral heterogeneity of the proto-oncogene Her-2/neu determined by three different detection systems. Breast J 1999; 5: Simmons C, Miller N, Geddie W, Gianfelice D, Oldfield M, Dranitsaris G, Clemons MJ: Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases. Ann Oncol 2009; 20(9): Liedtke C, Broglio K, Moulder S, Hsu L, Kau SW, Symmans WF, Albarracin C, Meric-Bernstam F, Woodward W, Theriault RL, Kiesel L, Hortobagyi GN, Pusztai L, Gonzalez-Angulo AM: Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer. Ann Oncol 2009, 20(12):

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