Printer Friendly

Gene Expression Profiling in Breast Cancer and Its Effect on Therapy Selection in Early-Stage Breast Cancer.

Introduction

Breast cancer is the type of cancer with the highest incidence rate among women globally and it ranks the first among reasons for death due to cancer in women (1). Appropriate selection and administration of therapies according to the patient are important for not only prolonging disease-free survival and overall survival, but also for preventing late complications (such as anthracycline-related cardiac problems, myelodysplastic syndrome, leukemia and taxane-associated neuropathy) (2).

It is a standard approach to administer adjuvant chemotherapy (CT) and/or hormonal treatment (HT) to reduce the risk for metastasis according to the histological, pathological and immunohistochemical staining characteristics of the tumor following surgical treatment of early-stage breast cancer (3-5). The strongest predictors in determining the risk for metastasis are as follows: tumor diameter, histological grade, axillary lymph nodes (ALN) metastasis and hormone receptors (HR) and HER2 status as well as Ki-67 proliferation index (6). In recent years, molecular sub-types (intrinsic sub-types) of breast cancer have been described and therapy selection is done according to these sub-types (7-10). Breast cancers are divided into four sub-groups as per their molecular characteristics (11, 12): Luminal, HER2-positive, basal and normal-like (Table 1). CT is necessary for adjuvant treatment of basal-type and HER2-positive breast cancer cases.

Luminal tumors are HR-positive breast cancers that constitute approximately 60-80% of all breast cancer cases (8, 11, 12). Luminal tumors are divided into two groups as A and B: Their characteristics are summarized in Table 2. While luminal A tumors are very sensitive to HT, it may be necessary to use CT and HT together in luminal B tumors. The above-specified classical predictors are not sufficient to distinguish between the luminal A and B sub-groups in HR-positive, HER2-negative breast cancer and does not account for different clinical progresses of luminal type breast cancer patients who are in the same stage and receive similar treatments. In order to explain this difference and better differentiate between patients who may not require chemotherapy as part of adjuvant therapy and those who need to have addition of CT to their hormone therapy, various gene expression analyses have been and are being studied retrospectively and prospectively.

Gene Expression Profiling

Amsterdam 70-gene Profile- MammaPrint dx Test (Table 3)

The first one of these tests is MammaPrint dx 70-gene expression analysis, which was developed by the Netherlands Cancer Institute. They identified 70 genes which differentiate between patients diagnosed with breast cancer as good profile and poor profile depending on the risk of developing metastasis within 5 years as of diagnosis. This gene profile was developed based on a gene study conducted with 78 ALN-negative patients below the age of 55 and diagnosed with invasive breast cancer a tumor size <5 cm (13, 14). The test is conducted using the micro-array-based gene expression profiling technique. Fresh tissue sample or frozen archival material and formalin-fixed paraffin-embedded (FFPE) material are used for the test (9, 15). Several studies have demonstrated that MammaPrint is an independent prognostic factor in patients with ALN-negative breast cancer (16-18). It has been seen that 35% of patients that seemed to have high risk disease actually had low risk and 14% of patients that seemed to be in the low risk group actually had high risk in this program as compared to the adjuvant online program (19).

The MammaPrint test is recommended for early breast cancer of all ages with tumor size <5 cm, with the ALN 0-3 positive cases, and estrogen receptor (ER)-positive or negative tumors (8). It was approved by Food and Drug Administration (FDA) in 2007 for marketing as a prognostic test, but not to select therapy or predict response to therapy (15). Results are reported as low risk (13% chance of developing distant metastases at 10 years without adjuvant treatment) or high risk (56% chance of developing distant metastases at 10 years without adjuvant treatment).

For the prospective validation of the test, an international, randomized, Phase-3 MINDACT study (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy-EORTC 10041/BIG 3-04 study) has been scheduled (20). In this study, 6693 patients with early-stage breast cancer (HR+, Nod 1-3 positive or negative, HER2-) were recruited. The genomic risks (using the 70-gene signature) and clinical-pathological risks (using a modified version of Adjuvant Online) of the patients were identified and the aim has been set as comparing their effectiveness in the adjuvant therapy selection. CT was not provided for the group with low genomic and clinical risk. CT was provided for the group with high genomic and clinical-pathological risk. In patients with discordant risk results, either the genomic risk or the clinical-pathological risk was used to determine the use of chemotherapy and hormone therapy or only hormone therapy. The primary aim of the study was to determine whether patients with high clinical risk and low genomic risk had requirement for CT. According to the assessment of 1550 patients with high clinical risk and low genomic risk, metastasis-free survival rate was found to be 94.7% in patients not receiving CT, which was 1.5% lower than the patients that were on CT. The rates of distant metastasis-free survival were found to be similar among patients that were node-negative or positive, ER-positive and HER2-. Based on these results, the researchers concluded that 46% of the patients with low genomic risk and high clinical risk did not require CT.

MammaPrint is featured as a prognostic parameter in the St Gallen and ESMO (European Society of Medical Oncology) guidelines (3, 21).

In the 8th Breast Cancer Staging System of American Joint Committee on Cancer (AJCC), which is to be published in 2018, gene expression profiling is included in breast cancer staging as a prognostic panel (22).

One of these panels is MammaPrint (when available as stage modifiers): For patients with HR-positive, HER2 negative , and ALN negative tumors, a MammaPrint low-risk score, regardless of T size, places the tumor in the same prognostic category as T1a-T1b N0M0 (Level of Evidence II).

21-Gene Recurrence Score assay (Oncotype DX) (Table 3)

The Oncotype DX Breast Cancer Assay is a commercially available reverse transcriptase-polymerase chain reaction (RT-PCR) based signature. It evaluates the mRNA levels of 21 genes (16 cancer-related genes and 5 reference genes) (8, 9, 15). The expression of these 21 genes is reported as a single Recurrence Score (RS), which ranges between 0 and 100. The test is routinely performed on FFPE tissue specimens.

Patients are divided into 3 risk groups depending on the risk for distant metastasis in ten years: 1- Low risk (RS<18) 2- Intermediate risk (RS 18-30) 3- High risk (RS>30)

The clinical validation of Oncotype DX was originally completed in 2 retrospective studies (National Surgical Adjuvant Breast and Bowel Project-NSABP B-14 and B-20 studies) (23, 24): In the NSABP B-14 study, patients (HR-positive disease with negative axillary nodes) were randomized to the tamoxifen versus placebo arms for 5 years (23). The distant metastasis-free survival rates of the patients as per their risk groups were as follows: Low risk group (RS<18; 10-year risk for distant metastasis: 6.8%); intermediate risk group (RS:18-30; 10-year risk for distant metastasis: 14.3%) and high risk group (RS>30; 10-year risk for distant metastasis: 30.5). In conclusion, Oncotype DX was interpreted as being a 'predictor of distant relapse in ER+ node negative disease.' These results were also tested in the NSABP B-20 study (HR positive disease with negative axillary nodes; adjuvant tamoxifen versus CMF + tamoxifen) and the contribution of CT as per the risk groups was investigated (24): It was seen that the addition of CT to tamoxifen for patients in the low risk group decreased the 10-year risk for distant metastasis by only 1.1% while the addition of CT to tamoxifen for patients in the high risk group reduced the 10-year risk for distant metastasis significantly by 27.6%. The benefit of the addition of CT to hormonal therapy in the intermediate risk group was not showed to be clinically significant.

The action to be taken for patients in the intermediate risk group could not be completely elucidated. Should it be only HT or CT and HT? In order to shed light onto this question, a prospective randomized study was initiated in the year 2006 (Trial Assigning Individualized Options for Treatment-TAILORx; prospective clinical validation study) (25). In this study, 10.253 patients (HR-positive and HER2-negative with negative axillary nodes) from 6 countries and 900 study sites were included between the years 2006 and 2010. The patients were divided into groups as follows: RS<11 low risk group (only endocrine treatment), RS 11-25 intermediate risk group (divided into two arms: only HT and CT + HT) and RS>25 high risk group (CT and HT). As part of HT, tamoxifen or aromatase inhibitor (AI) or tamoxifen followed by AI were administered for 5 years and tamoxifen or AI along with ovarian suppression were used in 3% of the patients. During the ESMO 2015 meeting, the results of the low-risk group (15.9% of all patients;-1626 patients) were presented as follows: 5-year invasive disease free survival: 93.8%; recurrence-free survival: 98.7%; distant recurrence-free survival: 99.3% and overall survival: 98%. Recurrence events were uncommon regardless of the histologic grade, tumor size and were not significantly affected by younger age at diagnosis in this low risk group.

The results of the study also prospectively showed that only adjuvant HT was sufficient for patients with low risk according to the 21 gene expression analysis (Level IA evidence). It is expected that the results of the intermediate risk group will be announced within the year 2017.

The prognostic and predictive validity of Oncotype DX was also retrospectively evaluated in 4 randomized phase-3 studies [SWOG 8814, ATAC (Adjuvant Tamoxifen or Anastrozole), NSABP-B28 and ECOG 2197 studies] including ALN positive and HR-positive cases (26-30). It was seen that CT was beneficial in distinguishing node-positive patients who would benefit from CT (Predictor of likelihood of chemotherapy benefit in ER+ Node positive disease). Its prospective validation in the node-positive patients was demonstrated in the West German Study Group Plan B Randomized Phase-3 study, the Clalit Registry study conducted in Israel and the SEER real-life observational study (31-33). In all these studies, the 5-year survival rate of patients in the low risk group is >95%.

Other ongoing trials (RxPONDER and OPTIMA) are evaluating whether adjuvant CT is beneficial in patients with HR-positive, HER2-negative breast cancer with 1 to 3 positive ALNs and a RS of 25 or less (7, 8).

Oncotype DX is included as a prognostic and predictive tests in the ESMO, St Gallen, NCCN (National Comprehensive Cancer Network; includes 1 to 3 positive nodes) and ASCO (American Society of Clinical Oncology; node negative only) guidelines (3, 4, 21, 34).

The Oncotype DX staging system has been included in the 8th breast staging system by AJCC (when available as stage modifiers) (22): For patients with HR-positive, HER2-negative and ALN-negative tumors, Oncotype DX recurrence score less than 11, regardless of T size, places the tumor in the same prognostic category as T1a-T1b N0M0, and the tumor is staged using the AJCC prognostic stage group table as stage I (Level of Evidence I).

Predictor analysis of microarray 50 risk of recurrence score (PAM50-ROR) (Table 3)

The PAM50 is a test that uses 50 classifier genes and 5 control genes. The microarray technique is employed and study is done on FFPE tissues with quantitative RT-PCR technology (8, 9, 15). Along with the tumor diameter and four main intrinsic sub-types are provided along with the risk of recurrence (ROR). The PAM50 score is reported on a 0-100 scale (ROR score of risk of recurrence), which is correlated with the probability of distant recurrence at ten years for women with HR positive, early-stage node-negative or node 1-3 positive breast cancer. Patients are divided into high (>20%), intermediate (10 to 20%) and low (<10%) risk groups. It was retrospectively tested in the ATAC and ABCSG-8(Austrian Breast Cancer Study Group 8) studies and demonstrated to be an important prognostic indicator for both ALN-negative and ALN-positive patients in all sub-groups (35, 36). It is an FDA-approved test (9, 34).

It has been included in the 8th breast cancer staging system by the AJCC (when available as stage modifiers) (22): For patients with HR-positive, HER2-negative and ALN-negative tumors, a PAM50 ROR score in the low-range, regardless of T size, places the tumor in the same prognostic category as T1a-T1b N0M0 (Level of Evidence II).

Breast Cancer Index (BCI) (Table 3)

Breast Cancer Index is a combination of molecular grade index (MGI) and HOXB13-to-IL17BR expression ratio (H:I ratio). Studies conducted have shown that it is effective in anticipating treatment response and prognosis in ER-positive tumors (37, 38). Three risk groups are identified: low, intermediate and high risk. Its clinical usability is still being investigated. ASCO states that it can be used in making a decision for adjuvant therapy in HR-positive, HER2-negative and node-negative disease while it is not recommended to be used in node-positive disease (34).

EndoPredict (Table 3)

It involves RNA-based analysis of 11 genes (8 cancer related and 3 reference genes). Its prognostic value was validated using the data from ABCSG-6 and ABCSG-8 trials (39). ASCO states that it can be used in making a decision for adjuvant therapy in HR-positive, HER2-negative and node-negative disease while it is not recommended to be used in node-positive disease (34). It is a test which can also be used to make a decision for prolonged adjuvant therapy.

Breast Cancer Index and EndoPredict (when available as stage modifiers) tests are also included as part of the prognostic panel in the 8th staging booklet (Level of evidence II) (22) (Table 3).

Other assays include the Rotterdam 76-gene signature, genomic grade index, molecular grade index, etc. There are not sufficient data about the prognostic significance of these arrays (9, 15, 34, 40, 41). Further studies are needed.

Conclusion

Gene expression analyses are beneficial in determining the prognosis and selecting therapy for luminal type breast cancers (HER2-negative, HR-positive). Even though these tests are costly, studies performed have shown that they are actually cost-efficient (42, 43). They are included in reimbursement schemes in the USA and Europe whereas they are not included in the reimbursement program in Turkey and many other countries. Therefore, studies can be conducted only on a limited group of patients. Studies conducted in Turkey have demonstrated that Oncotype DX has significantly correlated with PR and Ki-67 score of the tumor, and has a significant contribution to determining the therapy selection (44, 45). In another study from Turkey, Oncotype DX test was found as cost-effective in patients with early stage breast cancer (46).

It should also be kept in mind that gene expression analyses may yield false results in rarely seen tumors such as breast cancers showing neuroendocrine differentiation and in mixed morphologies (47). Furthermore, the stromal cells and inflammatory cells around the tumor tissue and the normal breast tissue are not included in the analysis. The ratio of non-neoplastic cells in the analysis may change the expression profile and the prognostic signature. In the second-generation gene expression analyses, myoepithelial and stromal cells are also assessed in addition to the epithelial cancer cells (8).

There are no gene expression tests available yet to determine the therapy selection for other intrinsic types of breast cancers. Various gene expression analyses and second generation gene expression analysis studies are ongoing with the aims of determining the drug selection in endocrine treatment, selecting the agent to be used in chemotherapy and predicting treatment to neoadjuvant therapy (8). Technological advancements and developments in the field of molecular biology and genetics will enable us to provide individualized therapies for our patients.

Peer-review: Externally peer-reviewed.

Conflict of Interest: No conflict of interest was declared by the author.

Financial Disclosure: The author declared that this study has received no financial support.

References

(1.) Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer Incidence and Mortality Worldwide: Sources, Methods and Major Pattern in GLOBOCAN 2012. Int J Cancer 2015; 136: 359-386. (PMID: 25220842) [CrossRef]

(2.) Davitson NE, Stearns V. Adjuvant Chemo Endocrine Therapy In. Harris JR, Lippman ME, Morow M, Osborne CK(eds). Disease of the Breast, 5th ed. Wolter Kluwer Health, Philadelphia, 2014.pp.649-668.

(3.) Coates AS, Winer EP, Goldhisch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thurlimamm B, Senn HJ, Panel Members. Tailoring Therapies-Improving the Mangement of early Breast Cancer: St Gallen International Expert Consensus on the Primary Therapy of early Breast Cancer 2015. Ann Oncol 2015; 26: 1533-1546. (PMID: 25939896) [CrossRef]

(4.) National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline in Oncology. Breast Cancer Version 2. 2017- April 6, 2017. Available from: NCCN.org

(5.) Gnant M, Harbeck N, Thomssen C. St Gallen/Vienna 2017: A Brief Summary of the Consensus Discussion about Escalation and De-Escalation of Primary Breast Cancer Treatment. Breast Care 2017; 12: 102-107. (PMID: 28559767) [CrossRef]

(6.) Masood S. Prognostic/Predictive Factors in Breast Cancer. Clin Lab Med 2005; 25: 809-825. (PMID: 16308094) [CrossRef]

(7.) Henry NL, Bedard PL, DeMichele A. Standart and Genomic Tools for Decision Support in Breast Cancer Treatment. Am Soc Clin Oncol Educ Book 2017; 37: 106-115. (PMID: 28561710). [CrossRef]

(8.) Verma A, Kaur J, Mehta K. Molecular Oncology Update: Breast Cancer Gene Expression Profiling. Asian J Oncol 2015; 1: 65-72. [CrossRef]

(9.) Rosa M. Advances in the Molecular Analysis of Breast Cancer: Pathway Toward Personalized Medicine. Cancer Control 2015; 22: 211-219. (PMID: 26068768) [CrossRef]

(10.) Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature 2000; 406: 747-752. (PMID: 10963602) [CrossRef]

(11.) Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J, Shi B. Breast Cancer Intrinsic Subtype Classification, Clinical Use and Future Trends. Am J Cancer Res 2015; 5: 2929-2943. (PMID: 26693050)

(12.) Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.Proc Natl Acad Sci USA 2001; 98: 10869-10874. (PMID: 11553815) [CrossRef]

(13.) van de Vijver MJ, He YD, van 't Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002; 347: 1999-2009. (PMID: 12490681) [CrossRef]

(14.) van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002; 415: 530-536. (PMID: 11823860) [CrossRef]

(15.) Reis-Filho JS, Pusztai L. Gene expression profiling in breast cancer: Classification, prognostication, and prediction. Lancet 2011; 378: 1812-1823. (PMID: 22098854) [CrossRef]

(16.) Buyse M, Loi S, van't Veer L, Viale G, Delorenzi M, Glas AM, d'Assignies MS, Bergh J, Lidereau R, Ellis P, Harris A, Bogaerts J, Therasse P, Floore A, Amakrane M, Piette F, Rutgers E, Sotiriou C, Cardoso F, Piccart MJ; TRANSBIG Consortium. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 2006; 98: 1183-1192. (PMID: 16954471) [CrossRef]

(17.) Mook S, Schmidt MK, Weigelt B, Kreike B, Eekhout I, van de Vijver MJ, Glas AM, Floore A, Rutgers EJ, van 't Veer LJ. The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol 2010; 21: 717-722. (PMID: 19825882) [CrossRef]

(18.) Knauer M, Mook S, Rutgers EJ, Bender RA, Hauptmann M, van de Vijver MJ, Koornstra RH, Bueno-de-Mesquita JM, Linn SC, van 't Veer LJ. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat 2010; 120: 655-661 (PMID: 20204499) [CrossRef]

(19.) Turaga K, Acs G, Laronga C. Gene Expression Profiling in Breast Cancer. Cancer Control 2010; 17: 177-182. (PMID: 20664515) [CrossRef]

(20.) Cardoso F, van't Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, Pierga JY, Brain E, Causeret S, DeLorenzi M, Glas AM, Golfinopoulos V, Goulioti T, Knox S, Matos E, Meulemans B, Neijenhuis PA, Nitz U, Passalacqua R, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Sotiriou C, Stork L, Straehle C, Thomas G, Thompson AM, van der Hoeven JM, Vuylsteke P, Bernards R, Tryfonidis K, Rutgers E, Piccart M; MINDACT Investigators. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med 2016; 375: 717-729. (PMID: 27557300) [CrossRef]

(21.) Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, Zackrisson S, Cardoso F; ESMO Guidelines Committee. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26: 8-30. (PMID: 28428927). [CrossRef]

(22.) Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, Weaver DL, Winchester DJ, Hortobagyi GN. Breast Cancer-Major Changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual. CA Cancer J Clin 2017; 67: 290-303. (PMID: 28294295)

(24.) Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Geyer CE, Jr, Wickerham DL, Wolmark N. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006; 24: 3726-3734. (PMID: 16720680) [CrossRef]

(25.) Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Perez EA, Olson JA Jr, Zujewski J, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin P, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Atkins JN, Berenberg JL, Sledge GW. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med 2015; 373: 2005-2014. (PMID: 26412349) [CrossRef]

(26.) Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, Ravdin P, Bugarini R, Baehner FL, Davidson NE, Sledge GW, Winer EP, Hudis C, Ingle JN, Perez EA, Pritchard KI, Shepherd L, Gralow JR, Yoshizawa C, Allred DC, Osborne CK, Hayes DF. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 2010; 11: 55-65. (PMID: 20005174) [CrossRef]

(27.) Dowsett M, Cuzick J, Wale C, Forbes J, Mallon EA, Salter J, Quinn E, Dunbier A, Baum M, Buzdar A, Howell A, Bugarini R, Baehner FL, Shak S. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol 2010; 28: 1829-1834. (PMID: 20212256) [CrossRef]

(28.) Mamounas EP, Tang G,Paik S , Baehner FL, Liu Q, Jeong J-H, Kim S-R, Butler SM, Jamshidian F, Cherbavaz DB, Shak S, Julian TB, Lembersky BC, Wickerham DL, Costantino JP, Wolmark N. Prognostic impact of the 21-gene recurrence score (RS) on disease-free and overall survival of node-positive, ER-positive breast cancer patients (pts) treated with adjuvant chemotherapy: Results from NSABP B-28. J Clin Oncol 2012; 30: 27 suppl 1-1.

(29.) Solin LJ, Gray R, Goldstein LJ, Recht A, Baehner FL, Shak S, Badve S, Perez EA, Shulman LN, Martino S, Davidson NE, Sledge GW Jr, Sparano JA. Prognostic value of biologic subtype and the 21-gene recurrence score relative to local recurrence after breast conservation treatment with radiation for early stage breast carcinoma: results from the Eastern Cooperative Oncology Group E2197 study. Breast Cancer Res Treat 2012; 134: 683-692. (PMID: 22547108) [CrossRef]

(30.) Brufsky AM. Predictive and Prognostic Value of the 21-Gene Recurrence Score in Hormone Receptor-positive, Node Positive Breast Cancer. Am J Clin Oncol 2014; 37: 404-410. (PMID: 24853663) [CrossRef]

(31.) Stemmer SM, Klang SH, Ben-Baruch N, Geffen DB, Steiner M, Soussan-Gutman L, Merling S, Svedman C, Rizel S, Lieberman N. The impact of the 21-gene Recurrence Score assay on clinical decision-making in node-positive (up to 3 positive nodes) estrogen receptor-positive breast cancer patients. Breast Cancer Res Treat 2013; 140: 83-92. (PMID: 23801158) [CrossRef]

(32.) Gluz O, Nitz UA, Christgen M, Kates RE, Shak S, Clemens M, Kraemer S, Aktas B, Kuemmel S, Reimer T, Kusche M, Heyl V, Lorenz-Salehi F, Just M, Hofmann D, Degenhardt T, Liedtke C, Svedman C, Wuerstlein R, Kreipe HH, Harbeck N. West German Study Group Phase III Plan B Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment. J Clin Oncol 2016; 34: 2341-2349. (PMID: 26926676) [CrossRef]

(33.) Roberts MC, Miller DP, Shak S, Petkov VI. Breast cancer-specific survival in patients with lymph node-positive hormone receptor-positive invasive breast cancer and Oncotype DX Recurrence Score results in the SEER database. Breast Cancer Res Treat 2017; 163: 303-310. (PMID: 28243896) [CrossRef]

(34.) Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzales-Angula AM, Hammond EH, Kuderer NM, Liu MC, Mennel RG, Poznak CV, Bast RC, Hayes DF. Use of Biomarkers to Guide Decision on Adjuvant Systemic Therapy for Women With Early Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016; 34: 1134-1150. (PMID: 26858339) [CrossRef]

(35.) Gnant M, Filipits M, Greil R, Stoeger H, Rudas M, Bago-Horvath Z, Mlineritsch B, Kwasny W, Knauer M, Singer C, Jakesz R, Dubsky P, Fitzal F, Bartsch R, Steger G, Balic M, Ressler S, Cowens JW, Storhoff J, Ferree S, Schaper C, Liu S, Fesl C, Nielsen TO; Austrian Breast and Colorectal Cancer Study Group. Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol 2014; 25: 339-345. (PMID: 24347518) [CrossRef]

(36.) Gnant M, Sestak I, Filipits M, Dowsett M, Balic M, Lopez-Knowles E, Greil R, Dubsky P, Stoeger H, Rudas M, Jakesz R, Ferree S, Cowens JW, Nielsen T, Schaper C, Fesl C, Cuzick J. Identifying clinically relevant prognostic subgroups of postmenopausal women with node-positive hormone receptor-positive early-stage breast cancer treated with endocrine therapy: a combined analysis of ABCSG-8 and ATAC using the PAM50 risk of recurrence score and intrinsic subtype. Ann Oncol 2015; 26: 1685-1691. (PMID: 25935792) [CrossRef]

(37.) Ma XJ, Salunga R, Dahiya S, Wang W, Carney E, Durbecq V, Harris A, Goss P, Sotiriou C, Erlander M, Sgroi D. A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer. Clin Cancer Res 2008; 14: 2601-2608. (PMID: 18451222) [CrossRef]

(38.) Jansen MP, Sieuwerts AM, Look MP, Ritstier K, Meijer-van Gelder ME, van Staveren IL, Klijn JG, Foekens JA, Berns EM. HOXB13-to-IL17BR expression ratio is related with tumor aggressiveness and response to tamoxifen of recurrent breast cancer: A retrospective study. J Clin Oncol 2007; 25: 662-668. (PMID: 17308270) [CrossRef]

(39.) Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, Dietze O, Greil R, Jelen A, Sevelda P, Freibauer C, Muller V, Janicke F, Schmidt M, Kolbl H, Rody A, Kaufmann M, Schroth W, Brauch H, Schwab M, Fritz P, Weber KE, Feder IS, Hennig G, Kronenwett R, Gehrmann M, Gnant M. EP Investigators. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res 2011; 17: 6012-6020. (PMID: 21807638) [CrossRef]

(40.) Syed MP, Kolluri S, Goffin JV, Tripathy D. Clinical Decision Making in Stage I and II Breast Cancer Patients Based on Gene Profiling. Am J Hematol/Oncol 2016; 12: 7-16.

(41.) Scope A, Essat M, Pandor A, Rafia R, Ward SE, Wyld L, Cross S, Woods HB. Gene expression profiling and expanded immunohistochemistry Tests to Guide Selection of Chemotherapy Regimens in Breast Cancer Management: A Systematic Review. Int J Technol Assess Health Care 2017; 10: 1-14. (PMID: 28486999)[CrossRef]

(42.) Kondo M, Hoshi SL, Yamanaka T, Ishiguro H, Toi M. Economic evaluation of the 21-gene signature (Oncotype DX) in lymph node-negative/positive, hormone receptor-positive early-stage breast cancer based on Japanese validation study (JBCRG-TR03) Breast Cancer Res Treat 2011; 127: 739-749. (PMID:21082239) [CrossRef]

(43.) Retel VP, Joore MA, Knauer M, Linn SC, Hauptmann M, Harten WH.Cost-effectiveness of the 70-gene signature versus St. Gallen guidelines and Adjuvant Online for early breast cancer. Eur J Cancer 2010; 46: 1382-1391. (PMID:20359886) [CrossRef]

(44.) ozmen V, Atasoy A, Gokmen E, ozdogan M, Guler N, Uras C, Ok E, Demircan O, Isikdogan A, Cabioglu N, Sen F, Saip P. Impact of Oncotype DX Recurrence Score on Treatment Decisions: Results of a Prospective Multicenter Study in Turkey. Cureus 2016; 8: 522. (PMID: 27081583)

(45.) ozmen V, Atasoy A, Gokmen E, ozdogan M, Guler N, Uras C, Ok E, Demircan O, Isikdogan A, Cabioglu N, Sen F, Saip P. Correlations Between Oncotype DX Recurrence Score and Classic Risk Factors in Early Breast Cancer: Results of A Prospective Multicenter Study in Turkey. J Breast Health 2016; 12: 107-111. (PMID: 28331745) [CrossRef]

(46.) Ozmen V, Gokmen E, Atasoy A, ozdogan M, Guler N, Uras C, Ok E, Demircan O, Isikdogan A, Saip P. Cost effectiveness of Oncotype DX test in patients with early-stage breast cancer in a middle-income country, Turkey: results of a prospective multicenter study. The Breast 2017; 32: 84-85. [CrossRef]

(47.) Tiberi D, Masucci L, Shedid D, Roy I, Vu T, Patocskai E, Robidoux A, Wong P. Limitations of Personalized Medicine and Gene Assays for Breast Cancer. Cureus 2017; 9: 1100. (PMID: 28428927) [CrossRef]

E. Nilufer Guler

Department of Medical Oncology, Hacettepe Cancer Institute, Ankara, Turkey

Address for Correspondence: E. Nilufer Guler, e-mail: nguler@hacettepe.edu.tr

Received: 09.06.2017

Accepted: 06.07.2017

DOI: 10.5152/ejbh.2017.3636

Cite this article as: Guler N. Gene Expression Profiling in Breast Cancer and Its Effect on Therapy Selection in Early-Stage Breast Cancer. Eur J Breast Health 2017; 13: 168-174.
Table 1. Breast cancer molecular subtypes (Modified from 11)

Intrinsic         IHC (*) status     Grade   Prognosis    Prevalence
subtype

Luminal A       ER+/PR+;HER2-;Ki67    1/2        Good         40%
                        low
Luminal B       ER+/PR+;HER2-;Ki67    2/3    Intermediate     20%
                       high
                ER+/PR+;HER2+;Ki67    2/3    Intermediate
                        any
HER2            ER-/PR-;HER2+;Ki67    2/3        Poor         12 to 21%
overexpression          any
Basal           ER-/PR-;HER2-;basal   3          Poor         11 to 23%
                      marker+
Normal-like      ER+/PR+;HER2-Ki67    1/2/3  Intermediate      3 to 10%
                        any

(*) IHC: Immuno-Histo-Chemical Staining; ER: Estrogen Receptor; PR:
Progesteron Receptor

Table 2: Characteristics of Luminal Subtypes Breast Cancers (Modified
from 8)

                                   Luminal A        Luminal B

Incidence %                            40              20
ER-related genes                      High       Relatively low
HER2-related genes                    Low           Variable
TP53 mutation                         12%              29%
Proliferation-related genes           Low             High
Prognostic significance               Good            Poor
Prediction to endocrine              Highly      Relatively less
therapy                            sensitive        sensitive
Prediction to cytotoxic therapy  Less sensitive  Less sensitive

ER: estrogen receptor

Table 3: Gene Expression Tests for Predicting Clinical Outcomes in
Patients with HR positive, HER2 negative, Node 0-3 Positive Early Stage
Breast Cancer (7, 9, 22, 34, 40)

                                                        PAM50-risk of
                   Oncotype DX         MammaPrint      recurrence score

Manufacturer      Genomic Health         Agendia          NanoString
                (Redwood City, CA)    (Irvine, CA)       Technologies
                                                        (Seattle, WA)
Tissue Sample          FFPE          Fresh, frozen,          FFPE
                                         or FFPE
No of genes         16 cancer              70             50 cancer
                    5 control                             22 control
                                                        /housekeeping
                                                         + tumor size
Technology         Quantitative        Microarrays       Quantitative
                      RT-PCR                                RT-PCR
Predictive              +                   -                 -
Prognostic              +                   +                 +
Eligible          ER+ and HER2-,       Stage I-and        ER+, stage
patients         T1/2 0-3 nodes f       II breast       I/II 0-3 nodes
                                         cancer
Measure                 RS            Good risk and      ROR:Ten year
/Categories          Low <18            poor risk        probability
                Intermediate 18-31      intrinsic         of distant
                       High              subtype          recurrence
                       >31                                 Low <10%
                                                         Intermediate
                                                            10-20%
                                                          High >20%
                                                          Intrinsic
                                                           subtype
Strength          Strong for N0       Moderate for      Strong for N0
of ASCO              Moderate           N0 and N+      Moderate for N+
recommendation        for N+
8th AJCC        For patients with     For patients    For patients with
breast cancer   HR-positive, HER2         with           HR-positive,
staging manual  negative, and ALN     HR-positive,      HER2 negative,
(when            negative tumors,    HER2 negative,    and ALN negative
available          Oncotype Dx      and ALN negative   tumors, a PAM50
as stage         recurrence score       tumors, a      ROR score in the
modifiers).       less than 11,        MammaPrint         low-range,
                 regardless of T     low-risk score,   regardless of T
                 size, places the    regardless of T   size, places the
                tumor in the same   size, places the  tumor in the same
                    prognostic        tumor in the        prognostic
                   category as       same prognostic     category as
                  T1a-T1b N0M0,        category as       T1a-T1b N0M0
                 and the tumor is     T1a-T1b N0M0    (Level of Evidence
                 staged using the       (Level of            II).
                 AJCC prognostic      Evidence II).
                   stage group
                 table as stage I
                    (Level of
                   Evidence I).

                        Breast
                     Cancer Index            EndoPredict

Manufacturer       bioTheranostics             Myriad
                                        /Sividon Diagnostics
Tissue Sample            FFPE                   FFPE
No of genes        MGI-5 cell cycle           8 cancer
                   genes; H/I-Gene            3 control
                   expression ratio
Technology           Quantitative           Quantitative
                        RT-PCR                 RT-PCR
Predictive                +                       -
Prognostic                +                       +
Eligible                 ER+                     ER+
patients                HER2-                   HER2-
                        Node-
Measure           Low, intermediate      The test result is
/Categories         and high risk          composed of the
                                       'molecular fingerprint'
                                            of a tumor in
                                        combination with the
                                       established prognostic
                                       parameters nodal status
                                           and tumor size
Strength           Moderate for N0         Moderate for N0
of ASCO             Strong for N+              and N+
recommendation    (don't use for N+)
8th AJCC          For patients with       For patients with
breast cancer     HR-positive, HER2         HR-positive,
staging manual    negative, and ALN        HER2 negative,
(when              negative tumors,       and ALN negative
available            a BCI in the        tumors, Endopredict
as stage        low-range, regardless      low-risk score,
modifiers).       of T size, places     regardless of T size,
                the tumor in the same    places the tumor in
                 prognostic category     the same prognostic
                   as T1a-T1b N0M0       category as T1a-T1b
                  (Level of Evidence       N0M0 (Level of
                         II).               Evidence II).

AJCC: American Joint Committee on Cancer; ALN: axillary lymph node;
ASCO: American Society of Clinical Oncology; FFPE: formaline-fixed
parafine embedded; RT-PCR: reverse transcriptase-polymerase chain
reaction; ER: estrogen receptor; HR: hormone receptor; BCI: Breast
Cancer Index; ROR: Risk of Recurrence
COPYRIGHT 2017 AVES
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2017 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Guler, E. Nilufer
Publication:European Journal of Breast Health
Date:Oct 1, 2017
Words:5686
Previous Article:Reliable Biomarkers to Identify New and Recurrent Cancer.
Next Article:The Effects of Training on Knowledge and Beliefs About Breast Cancer and Early Diagnosis Methods Among Women.
Topics:

Terms of use | Privacy policy | Copyright © 2020 Farlex, Inc. | Feedback | For webmasters