REVIEW EDITORIAL For reprint orders, please contact:
[email protected]
Clinical implications of intratumoral heterogeneity of HER2 gene amplification in locally advanced HER2-positive breast cancer patients “HER2 expression and hormone receptors may subsequently become negative following neoadjuvant chemotherapy treatment.” Bekir Hacioglu1, Serkan Akin1, Ali R Sever2 & Kadri Altundag*,1 HER2-positive breast cancer is a biologically heterogeneous disease with different characteristics and clinical outcomes. HER2 is a transmembrane receptor that belongs to the ErbB/HER family of receptor tyrosine kinases. HER2 is amplified and HER2 protein is overexpressed in 20–30% of breast cancers. Tumors that have gene amplification or protein overexpression of HER2 are among the most aggressive and are associated with poor clinical outcomes compared with tumors that do not have HER2 overexpression. HER2 protein expression should be evaluated in the tumors of all patients with newly diagnosed primary invasive breast cancer, because of its prognostic and predictive value, either by immunohistochemistry (IHC) or in situ hybridization. The current American Society of Clinical Oncology/College of American Pathologists guidelines, updated in 2013, define HER2 positivity as 3+ on IHC (defined as uniform intense membrane staining of >10% of invasive tumor cells) or amplified on in situ hybridization (an HER2: chromosome enumeration probe 17 ratio of >2.0, or 6 signals/cell) [1] . Neoadjuvant chemotherapy is defined as chemotherapy administered as initial treatment before definitive surgical
intervention or irradiation. Neoadjuvant chemotherapy has traditionally been used in breast cancer to treat patients with locally advanced/inoperable disease, to facilitate surgical resection and to allow breast-conserving surgery in women with larger tumors who are not candidates for such surgery at presentation. In recent years, there has been a growing interest in the neoadjuvant approach for early and locally advanced breast cancer. There are several advantages of neoadjuvant chemotherapy, compared with the classical adjuvant treatment. One of them is the opportunity to monitor response during treatment, and it allows changing or discontinuing treatment in case of nonresponsiveness. Even if an advantage by changing therapy has not yet been proven, toxicity of an ineffective treatment can be avoided. The demonstration of treatment efficacy, conversely motivates patients to continue therapy despite toxicities. The other one is the rate of breast conservation that can be increased, so the extent of surgery can be reduced by doing breast conserving therapy. Additionally, primarily inoperable tumors can be downsized allowing a curative intervention. Another advantage is the opportunity to see the residual cancer burden that is a powerful prognostic marker, sometimes changing
KEYWORDS
• adjuvant • breast cancer • chemotherapy • complete remission • HER2-positive • intratumoral heterogeneity • locally advanced • neoadjuvant • receptors • trastuzumab
“HER2-positive breast cancer is a biologically heterogeneous disease with different characteristics and clinical outcomes.”
Department of Medical Oncology, Hacettepe University Cancer Institute, 06100 Ankara, Turkey Department of Radiology, Hacettepe University School of Medicine, Ankara, Turkey *Author for correspondence: Tel.: +90 312 3052939; Fax: +90 312 3242009;
[email protected] 1 2
10.2217/fon.15.164 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(18), 2495–2497
part of
ISSN 1479-6694
2495
Editorial Hacioglu, Akin, Sever & Altundag
“...more research is needed
for patients who were initially positive but subsequently had negative HER2 status due to neoadjuvant treatment.”
the initial prognostic profile in either way. The last is, in neoadjuvant trials, mechanisms of resistance predictive markers, tumor biology and new treatment approaches can be investigated more rapidly and with fewer patients than in adjuvant studies. Patients achieving a pathologic complete remission (pCR) showed a better long-term outcome, in many neoadjuvant trials, indicating pCR as a strong prognostic marker, which is particularly true in cases when the breast as well as axillary lymph nodes are free of invasive carcinoma [2] . There is controversy regarding the effectiveness of neoadjuvant chemotherapy in promoting overall survival in breast cancer; however, many of its advantages have been accepted and integrated into clinical treatments. Equivalent survival in the two treatment modalities have been demonstrated in several clinical trials comparing neoadjuvant chemotherapy with postoperative therapy [3] . The biologic agent trastuzumab is an HER2targeted monoclonal antibody that inhibits the proliferation of tumor cells and induces tumor cell death through multiple mechanisms of action. Currently, trastuzumab is approved
ADVANCING ONCOLOGY TOGETHER Find out how; join our online community today 2496 www.Oncology-Central.com Future Oncol. (2015) 11(18)
for use in the adjuvant, neoadjuvant and metastatic settings. Trials combining trastuzumab with neoadjuvant chemotherapy is shown to dramatically increase the rate of pathological complete response in HER2-positive breast cancer cases [4] . Multiple encouraging anti-HER2 drugs with different mechanisms of action have recently been developed. Combined administration of two different HER2-targeted agents shows enhanced antitumor activity, with an increase in pCR to the values never reached in the past. This combination is, trastuzumab with lapatinib or pertuzumab, and primary chemotherapy. Moreover, results of recent studies show that the combination of targeted therapy alone, without the addition of chemotherapy, also has activity in a substantial percentage of patients. This combination can eradicate HER2-positive tumors without chemotherapy and its toxicity profile is favorable [5] . Neoadjuvant chemotherapy followed by cytoreduction surgery has currently become part of standard care for patients with locally advanced breast cancer. In general, neoadjuvant chemotherapy causes a recognizable impact on the immunohistochemical expression of different tumor biomarkers, tumor grade, properties of the tumor cells and tumor proliferation rates in breast cancer specimens [6,7] . Biomarker levels of estrogen receptor, progesterone receptor, HER2 and Ki-67 changes differentially, following various neoadjuvant treatments. These changes may affect treatment decisions, as changes in cellular proliferation and hormone receptors have been shown to be associated with tumor response. Indeed, neoadjuvant chemotherapy can reduce the immunohistochemical expression of HER2 and in some subsets the postsurgical specimens may become negative [3,7] . Recent trials demonstrated that with neoadjuvant chemotherapy, a change of 8–33% in hormone receptor status after neoadjuvant chemotherapy was reported. During neoadjuvant chemotherapy, HER2 seems to be more stable than the hormone receptors. While using FISH to test HER2, discordance was only reported in one of the trials. By contrast, when neoadjuvant chemotherapy was combined with trastuzumab, up to 43% of the patients showed no HER2 amplification in the residual tumor. One of the possible mechanisms for a change in receptor status or expression in breast cancer cells caused by chemotherapy is, targeting chemosensitive tumor cells leaves insensitive tumor cells with different biology behind in
future science group
Clinical implications of HER2 gene amplification in locally advanced breast cancer patients the residual disease. Another mechanism may be the change in receptor status and biology as a survival mechanism of tumor cells, leading to resistance of a specific therapy [8] . And also, this biological discordance may be related to intratumoral heterogeneity. Intratumoral heterogeneity of HER2 gene amplification is of more importance especially in patients with low-grade HER2 amplification or with equivocal HER2 expression, indicating the need for HER2 testing on more representative, larger tumor samples for accurate assessment of HER2 status. Patients with this heterogeneity have decreased diseasefree survival, suggesting that genetic instability, and hence aberrant HER2 amplification in subclones of such tumors, may be associated with breast cancer progression [6,7] . We suggest that such patients should still be treated with HER2-targeted therapy at adjuvant treatment, relying on the fact that these tumors showed HER2 positivity at the time of the initial diagnosis. Future perspective HER2 expression and hormone receptors may subsequently become negative following References
1
2
3
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. 31, 3997–4013 (2013). Gampenrieder SP, Rinnerthaler G, Greil R. Neoadjuvant chemotherapy and targeted therapy in breast cancer: past, present, and future. J. Oncol. 2013 732047 (2013). Jin G, Han Y, Liu C et al. Evaluation of biomarker changes after administration of various neoadjuvant chemotherapies in breast cancer. Int. J. Clin. Exp. Pathol. 8(1), 914–921 (2015).
future science group
neoadjuvant chemotherapy treatment. Currently, the tests which identify the HER2 expression are IHC, FISH and silver-enhanced in situ hybridization. More sensitive diagnostic methods are required to reveal HER2 expression, which is not negative, yet cannot be detected by current methods in the postoperative pathological specimen. Also, more research is needed for patients who were initially positive but subsequently had negative HER2 status due to neoadjuvant treatment. A robust comparison needs to be conducted between these two groups with anti-HER2 therapy and the group with no anti-HER2 therapy in patients who subsequently became HER2 negative. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
4
Chang HR. Trastuzumab-based neoadjuvant therapy in patients with HER2-positive breast cancer. Cancer 116, 2856–2867 (2010).
5
Pernas Simon S. Neoadjuvant therapy of early stage human epidermal growth factor receptor 2 positive breast cancer: latest evidence and clinical implications. Ther. Adv. Med. Oncol. 6(5), 210–221 (2014).
6
Seol H, Lee HJ, Choi Y et al. Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod. Pathol. 25, 938–948 (2012).
•
Indicates that the changes in HER2 expression may be associated with intratumoral heterogeneity.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
7
Editorial
Avci N, Deligonul A, Tolunay S et al. Neoadjuvant chemotherapy-induced changes in immunohistochemical expression of estrogen receptor, progesterone receptor,
HER2, and Ki-67 in patients with breast cancer. J. BUON. 20, 45–49 (2015). •
Specifies that neoadjuvant chemotherapy may induce the changes in HER2 expression in patients with breast cancer. These references particularly indicate the incidence of changes in HER2 expression due to anti-HER2 treatment.
8
Van de Ven S, Smit VT, Dekker TJ et al. Discordances in ER, PR and HER2 receptors after neoadjuvant chemotherapy in breast cancer. Cancer Treat. Rev. 37(6), 422–430 (2011).
•
Specifies that neoadjuvant chemotherapy may induce the changes in HER2 expression in patients with breast cancer. These references particularly indicate the incidence of changes in HER2 expression due to anti-HER2 treatment.
www.futuremedicine.com
2497
