metastatic breast cancer: monitoring soluble her2 levels · metastatic breast cancer in younger...

Metastatic Breast Cancer: Monitoring Soluble HER2 Levels

Complimentary CME

Program DescriptionHER2/neu-positive tumors account for approximately 20% of all breast cancers and these tumors carry poor prognosis. In HER2/neu-positive breast cancer, the HER2 receptor is believed to be the main driving force responsible for tumor cell proliferation, metastatic potential and poor survival. Accordingly, therapeutic targeting of HER2/neu has the potential benefit to offset the signaling process initiated by the HER2 over-expression, thus reversing the malignant features of these tumors. Agents targeting HER2 have been shown to be associated with improvement in response rate, disease free, and overall survival.

This article will discuss the data regarding the incidence of metastatic breast cancer in younger aged women and the importance of HER2 detection in breast cancer. It will also cover the data of soluble HER2 monitoring in HER2+ patients with metastatic breast cancer and appropriate patient counseling strategies to raise patient awareness of the role of HER2 monitoring in breast cancer.

Learning ObjectivesAfter completion of this activity, participants will be able to:

• Describe the data regarding the incidence of metastatic breast cancer

• Discuss the importance of HER2 detection in breast cancer

• Define the data of soluble HER2 monitoring in HER2+ patients with metastatic breast cancer

• Identify appropriate patient counseling strategies to raise patient awareness of the role of HER2 monitoring in breast cancer

Target AudienceThis course is designed to meet the Continuing Medical Education needs of the practicing breast oncologist, general oncologist, oncology nurse, and women’s health clinician.

Disclosure of Conflicts of Interest TOPEC and Omnia Education assess conflict of interest with its faculty, planners, authors and reviewers of CME activities. If conflicts of interest are identified for anyone who is in a position to control content, the conflicts are thoroughly vetted and resolved in part by the use of independent reviewers who review content for fair balance, scientific objectivity of studies utilized in the activity and patient care recommendations. TOPEC and Omnia Education are committed to providing its learners with high quality, unbiased and state-of-the-art education.

The following faculty has reported real or apparent conflicts of interest that have been resolved:• Nirupama Mulherkar, PhD, has nothing to

disclose.

The following reviewers and planners have reported real or apparent conflicts of interest that have been resolved:• Edward R. Sauter, MD, PhD, MHA, has

nothing to disclose.

• Barry A. Fiedel, PhD, has nothing to disclose.

• Amanda Hilferty has nothing to disclose.

• Sean T. Saunders, CCMEP, has nothing to disclose.

• Robert Schneider has nothing to disclose.

AccreditationThe Omnia-Prova Education Collaborative, Inc. is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit DesignationThe Omnia-Prova Education Collaborative, Inc. designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Commercial SupportThis activity is supported by an independent educational grant from Nuclea.

IntroductionGlobally, breast cancer is the most frequently diagnosed malignancy and is the leading cause of cancer-related death in women.1 Recent estimates indicate that breast cancer has the highest incidence in North America, with prevalence in the United States (US) reported as 2.8 million in 2011. Based on age-adjusted rates, the data from 2007-2011 indicate that the number of new cases of breast cancer was 124.6 per 100,000 women per year and the number of deaths was 22 per 100,000 women per year. Based on 2009-2011 statistics, the lifetime risk of developing breast cancer among women is 12.3%.2 According to the American Cancer Society, in 2014, breast cancer will represent 14% of all new cancer cases and 6.8% of all cancer deaths in women.3 For the year 2014, approximately 235,030 new cases of breast cancer are estimated and 40,430 women are expected to die from breast cancer, in the US. Although 89.2% people are known to survive breast cancer 5 years after diagnosis, survival is dependent on the stage at diagnosis. The 5 year relative survival for localized, regional, distant and unstaged breast cancer is 98.5%, 84.6%, 25.0%, and 49.8%, respectively. Metastatic breast cancer (MBC) is thus associated with the worst 5 year relative survival.2 [Figure 1]. A recent study demonstrated that the incidence of MBC has increased among women between 25-39 years of age. The incidence of MBC in women aged 25-39 years was 1.53 per 100,000 women in 1976, and in 2009, the incidence of MBC in the same age group was 2.9 per 100,000 women. This annual percent change in incidence of MBC is 2.07 (95% CI 1.57 to 2.58) (P <0.001) and has been reported in all races and ethnicities.4 These statistics indicate a need for molecular determinants that can predict response to therapy and clinical outcomes in breast cancer, especially in MBC.

HER2 in Breast CancerIn approximately 20% of breast cancers, human epidermal growth factor receptor 2 (HER2) protein levels are overexpressed from amplification of the HER2 gene as compared with normal cells. HER2 positivity in breast cancer is defined as evidence of protein overexpression or gene amplification (HER2 copy number or HER2/CEP17 ratio). HER2-positive breast cancers have been associated with poor prognosis and survival from increased tumor cell proliferation, and metastatic potential as result of increased signaling through the HER2 receptor.5,6 In some instances, HER2 positivity has been shown to predict resistance or sensitivity to anthracyclines and taxanes and also resistance to certain endocrine therapies.7 Given its important role in a subset of breast cancers, antibodies (trastuzumab, pertuzumab) and inhibitors (lapatinib, neratinib) targeting HER2 have been developed that can inhibit signaling through the HER2 receptor. The Food and Drug Administration (FDA) has approved trastuzumab in combination with paclitaxel; trastuzumab chemically linked to cytotoxic mertansine (DM1); pertuzumab in combination with trastuzumab and docetaxel in HER2 positive breast cancer; and lapatinib in combination with letrozole in postmenopausal women with hormone receptor and HER2-


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FIGURE 1

positive MBC.8 Treatment with HER2 targeted therapy has been associated with improved response rate, disease free and overall survival in patients with HER2-positive cancers. Determining HER2 status is therefore crucial to guide therapy in the neoadjuvant, adjuvant, and MBC setting in order to identify patients that can benefit from HER2 targeted therapy.7

HER2 Detection in TissueHER2 can be detected in tissue with a combination of immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH). While this test is semi-quantitative, it is essential and currently recommended for establishing correct HER2 status of tumors. Testing criteria for HER2-positive status include evidence of overexpression of HER2 in IHC within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells or gene amplification of HER2 copy number or HER2/CEP17 ratio by FISH based on counting at least 20 cells within the area.9,10 However, evaluation by IHC and FISH have been associated with inconsistencies between the HER2 statuses of primary versus metastatic tumors. To that end, some patients with primary tumors classified as HER2-negative have been reported to develop recurrent HER2-positive metastatic tumor.11 Indeed, misclassification of HER2 status has also been reported, and an average of 20% (range of 10-40%) HER2-negative tumors are believed to be misclassified. This misclassification has been attributed to limitations in testing as well as tumor drift and has been either evidenced with alternative HER2 testing approaches or with the presence of HER2-positive circulating tumor cells or in the metastatic setting. Misclassification of HER2 status can have serious therapy-related implications due to a lack of access to HER2 targeted therapies.7 Therefore, there has been a need for alternative and reliable HER2 testing approaches.

Serum HER2 TestThe serum HER2 test measures the extracellular domain of the HER2 protein (sHER2) released in the blood of both normal individuals as well as individuals with breast cancer. This is a quantitative ELISA test [Figure 2] in which sHER2 levels ≥15 ng/mL and a change of 20% or more between 2 successive blood draws indicates HER2 positivity and progression, respectively.12 Using this test, up to 90% of HER2-positive MBC and 10-15% of primary early stage breast cancers have sHER2 levels ≥15 ng/mL, thereby indicating higher sensitivity in MBC.13,14 Elevated sHER2 has been detected as early as up to 24 weeks before other signs of disease progression. In addition, while persistently elevated sHER2 levels are indicative of poorer progression free and overall survival after recurrence, decrease in elevated sHER2 levels is indicative of better progression free survival and longer survival after recurrence.7,15,16 [Figure 3]. This has been confirmed in a meta-analysis that demonstrated elevated



FIGURE 2 FIGURE 3

sHER2 in a mean of 18.5% HER2-positive early stage breast cancer and a mean of 43% HER2-positive MBC. This meta-analysis also corroborated that higher circulating sHER2 correlates with inferior progression free and overall survival, and poor response to therapy. Similarly, a serial increase in sHER2 preceded the appearance of metastases and longitudinal sHER2 changes predicted the clinical course of underlying disease.12 [Figure 4]. The sHER2 test has also shown promise in monitoring of MBC and in determining response to trastuzumab and lapatinib therapy.17-20 This test was approved by the FDA in 2000 for use in the management and monitoring of women with MBC.21 Despite FDA approval, some studies do not recommend the sHER2 test for clinical use due to variability in the clinical prevalence of increased concentrations of sHER2 and inconsistencies in correlation with clinical outcomes.22,23 The most recent American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) guidelines for HER2 testing in breast cancer do not recommend sHER2 testing for clinical use.9 Indeed, larger sHER2 clinical studies are therefore warranted to clarify the role of sHER2 testing. In spite of the controversies, a plethora of studies support the utility of sHER2 testing as a complement to IHC/FISH in early stage disease, and as a prognostic indicator to assess response to treatment in MBC patients.7

SummaryHER2 status is an important clinical parameter in guiding therapeutic decisions and outcomes in breast cancer. However, there have been reports of misclassification of HER2 status in breast cancer with immunohistochemistry and fluorescence in-situ hybridization. The serum HER2 test can be used as an aid to complement HER2 tumor status. In addition, serum HER2 levels can assist in disease prognosis for patients with MBC, with serum HER2 ≥15ng/mL being an indicator for poor outcomes and lower levels indicating better clinical outcomes.

references: 1. Globocan 2012. Fast Stats. Most frequent cancers: both sexes. Accessed December 2014. 2. SEER Stat Fact Sheets: Breast Cancer. http://seer.cancer.gov/statfacts/html/breast.html Accessed December 2014. 3. American Cancer Society Facts & Figures 2014. 4. Johnson RH, Chien FL, Bleyer A. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009.

Jama. 2013;309(8):800-805. 5. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer:

American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med. 2014;138(2):241-256.

6. Brufsky AM, Mayer M, Rugo HS, et al. Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin Cancer Res. 2011;17(14):4834-4843.

7. Carney WP, Bernhardt D, Jasani B. Circulating HER2 Extracellular Domain: A Specific and Quantitative Biomarker of Prognostic Value in all Breast Cancer Patients? Biomark Cancer. 2013;5:31-39.

8. Li SG, Li L. Targeted therapy in HER2-positive breast cancer. Biomed Rep. 2013;1(4):499-505. 9. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast

cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-4013.

10. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25(1):118-145.

11. Ardavanis A, Kountourakis P, Kyriakou F, et al. Trastuzumab plus paclitaxel or docetaxel in HER-2-negative/HER-2 ECD-positive anthracycline- and taxane-refractory advanced breast cancer. Oncologist. 2008;13(4):361-369.



FIGURE 4

12. Carney WP, Neumann R, Lipton A, Leitzel K, Ali S, Price CP. Potential clinical utility of serum HER-2/neu oncoprotein concentrations in patients with breast cancer. Clin Chem. 2003;49(10):1579-1598.

13. Tse C, Brault D, Gligorov J, et al. Evaluation of the quantitative analytical methods real-time PCR for HER-2 gene quantification and ELISA of serum HER-2 protein and comparison with fluorescence in situ hybridization and immunohistochemistry for determining HER-2 status in breast cancer patients. Clin Chem. 2005;51(7):1093-1101.

14. Moreno-Aspitia A, Hillman DW, Dyar SH, et al. Soluble human epidermal growth factor receptor 2 (HER2) levels in patients with HER2-positive breast cancer receiving chemotherapy with or without trastuzumab: results from North Central Cancer Treatment Group adjuvant trial N9831. Cancer. 2013;119(15):2675-2682.

15. Bramwell VH, Doig GS, Tuck AB, et al. Changes over time of extracellular domain of HER2 (ECD/HER2) serum levels have prognostic value in metastatic breast cancer. Breast Cancer Res Treat. 2009;114(3):503-511.

16. Finn RS, Gagnon R, Di Leo A, Press MF, Arbushites M, Koehler M. Prognostic and predictive value of HER2 extracellular domain in metastatic breast cancer treated with lapatinib and paclitaxel in a randomized phase III study. J Clin Oncol. 2009;27(33):5552-5558.

17. Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2009;27(34):5838-5847.

18. Petersen ER, Sorensen PD, Jakobsen EH, Madsen JS, Brandslund I. Serum HER-2 predicts response and resistance to trastuzumab treatment in breast cancer. Clin Chem Lab Med. 2013;51(7):1483-1492.

19. Ali SM, Carney WP, Esteva FJ, et al. Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Cancer. 2008;113(6):1294-1301.

20. Lipton A, Leitzel K, Ali SM, et al. Human epidermal growth factor receptor 2 (HER2) extracellular domain levels are associated with progression-free survival in patients with HER2-positive metastatic breast cancer receiving lapatinib monotherapy. Cancer. 2011;117(21):5013-5020.

21. Carney WP, Leitzel K, Ali S, Neumann R, Lipton A. HER-2/neu diagnostics in breast cancer. Breast Cancer Res. 2007;9(3):207.22. Leyland-Jones B, Smith BR. Serum HER2 testing in patients with HER2-positive breast cancer: the death knell tolls. Lancet Oncol.

2011;12(3):286-295.23. Leary AF, Hanna WM, van de Vijver MJ, et al. Value and limitations of measuring HER-2 extracellular domain in the serum of breast cancer

patients. J Clin Oncol. 2009;27(10):1694-1705.



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metastatic breast cancer: monitoring soluble her2 levels · metastatic breast cancer in younger...

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