August 2012, Vol 1, No 3
Which Breast Cancer Patients Should Receive Adjuvant Chemotherapy?
At the 2012 conference of the Global Biomarkers Consortium, which took place March 9-11, 2012, in Orlando, Florida, Alvaro Moreno-Aspitia, MD, from the Mayo Clinic in Jacksonville, Florida, discussed the use of personalized therapy in the management of breast cancer.
- A number of decision-making tools have become available to help clinicians and patients with early cancer discuss the risks and benefits of getting adjuvant therapy after surgery
- Adjuvant! Online 8.0 estimates the risk of negative outcome (cancer-related mortality or relapse) without systemic adjuvant therapy, the reduction of these risks afforded by therapy, and the risks of side effects of the therapy
- Gene-profiling assays, such as Oncotype DX and MammaPrint, are commercially available to help identify patients at high risk of recurrence
Prognostication in breast cancer is an inexact science, with tumor (and patient) heterogeneity likely contributing to this lack of prognostic precision. For example, even in patients traditionally considered at low risk for recurrence (ie, those who are T1, N0, ER+), about 15% will have a recurrence within 10 years with tamoxifen treatment alone.1 Therefore, much interest surrounds the field of personalized medicine, which aims to identify patients at high risk of recurrence and to tailor therapy specifically for those patients. It is hoped that personalized medicine will bring to the clinic newer drugs that target this high-risk population and avoid overtreating patients who have an overall good prognosis, and avoid costly side effects as well.
- A 52-year-old woman recently underwent surgery for a stage IA, 1.5-cm, right breast tumor (grade 2 invasive ductile carcinoma, estrogen receptor [ER]-positive, progesterone receptor [PR]-positive, and HER2-negative)
- Her biopsy showed no vascular invasion, negative surgical margins, and 2 negative lymph nodes
- You feel she should receive adjuvant radiation therapy and endocrine therapy, but how do you decide whether she should receive adjuvant chemotherapy?
- What if the patient in our case has 2 macroscopically (0.5 cm each without extracapsular extension) involved sentinel lymph nodes?
Over the past decade, a number of decision-making tools have become available to help healthcare professionals and patients with early cancer discuss the risks and benefits of getting adjuvant therapy after surgery. One of these tools is Adjuvant! Online 8.0,2 a Web-based validated tool that predicts 10-year outcomes with and without adjuvant systemic therapy for patients with early breast cancer.3,4 Adjuvant! Online incorporates the updated St. Gallen consensus guidelines,5 the National Comprehensive Cancer Network guidelines,6 the Update of the Oxford Overview,7 the Early Breast Cancer Trialists’ Collaborative Group meta-analysis,8 as well as clinical trial information in the literature and reported at major breast cancer meetings, including information on the 7 major aromatase inhibitor trials, the 5 major adjuvant trastuzumab trials, and the new trials that incorporate taxanes into adjuvant therapy.
When a patient’s data (eg, patient age, tumor size, nodal involvement, histologic grade, etc) are entered into Adjuvant! Online, the program estimates the risk of negative outcome (cancer-related mortality or relapse) without systemic adjuvant therapy, the reduction of these risks afforded by therapy, and the risks of side effects of the therapy. These estimates are then provided on printed sheets in simple graphic and text formats to be used in consultations with patients and may be useful in supporting decision making.
Gene Profiling of Tumor
Because the patient’s father had a rough time with chemotherapy for lung cancer, the patient still wasn’t convinced, and asked, “Is there anything else that you can provide to help me make a decision?” Indeed, several genomic assays are commercially available (Table 1). Among these gene-profiling assays, Oncotype DX and MammaPrint are the most mature.
The Oncotype DX assay analyzes the expression of 21 genes by reverse transcriptase-polymerase chain reaction to provide an individualized Recurrence Score (RS; from 0 to 100) for each patient.9,10 In addition to quantifying breast cancer recurrence risk, the Oncotype DX assay also assesses the benefit from chemotherapy.
Node-Negative, ER-Positive Breast Cancer
The data from which the assay was developed were retrospectively analyzed from a prospective randomized trial known as the National Surgical Adjuvant Breast and Bowel Project Study B-20, which compared the combination of chemotherapy (ie, 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil) plus hormonal therapy (ie, tamoxifen) with hormonal therapy alone in 651 women with lymph node–negative, ER-positive breast cancer. Patients with an RS lower than 18 are categorized as low risk. These patients do well, with over 90% of patients alive at 10 years. Patients with an RS of 31 or higher are considered as high risk of recurrence. Those with scores in the middle (18 to <31) are classified as intermediate risk (Figure 1).9
When the Oncotype DX assay was used for the patient in this case, an RS of 27 was obtained, which put her in the intermediate-risk group (Figure 2). In that case, her risk of distant recurrence is about 17%, which is actually similar to the estimated recurrence rate found with Adjuvant! Online.
Node-Positive, ER-Positive Postmenopausal Breast Cancer
For lymph node–positive, ER-positive postmenopausal patients treated with tamoxifen, the Oncotype DX report form now includes data retrospectively analyzed from the prospective randomized Southwest Oncology Group (SWOG) 8814 study, which evaluated the risk of recurrence or death versus the RS result (both prognosis and likelihood of chemotherapy benefit). In the SWOG 8814 study, 1477 women were randomized to receive either tamoxifen alone for 5 years (n=361), or 6 cycles of chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) with concurrent tamoxifen (n=550), or 6 cycles of CAF followed by tamoxifen (CAF-T).11 Among the groups of women with RS <18 (the low-risk group) or 18 to 30 (intermediate-risk group), CAF-T offered no significant advantage over the 10-year disease-free or overall survival rates seen among those who received tamoxifen alone. In contrast, among the women who had RS ≥31, the 10-year disease-free and overall survival rates were significantly greater with CAF-T than with tamoxifen alone.
Prospective, Randomized Trials Under Way
While the Oncotype DX is currently based on retrospective data from the 2 aforementioned prospective randomized clinical trials, prospective studies are ongoing. One prospective study, known as the Trial Assigning Individualized Options for Treatment (Rx) (TAILORx), is examining whether chemotherapy is required for the intermediate-risk group defined by the RS.12 Another prospective randomized trial, known as the Rx for Positive Node, Endocrine Responsive Breast Cancer (RxPONDER, or SWOG S1007) study, opened in January 2011 and will assess whether chemotherapy benefits patients with node-positive breast cancer who have low to intermediate RS. The trial will also examine whether there is an optimal RS cutoff point for these patients, above which chemotherapy should be recommended. This study includes women with RS ≤25 who have early-stage, hormone receptor–positive, HER2-negative breast cancer that has been found to involve 1 to 3 lymph nodes.
MammaPrint analyzes 70 genes that comprise a definitive gene expression signature and stratifies patients to 1 of 2 groups: those with low risk of distant recurrence (good signature group) and those with high risk of
distant recurrence (poor signature group).13 With MammaPrint, there are no intermediate results. Patients who have a good signature do quite well, with less than 20% experiencing a relapse 10 years after their diagnosis, while patients with a poor signature do poorly overall, with about 50% to 60% experiencing relapse.14 Key differences between MammaPrint and Oncotype DX are listed in Table 2.
MammaPrint is being evaluated in a clinical trial known as Microarray In Node-negative and 1-3 positive lymph node Disease may Avoid ChemoTherapy (MINDACT), which is a randomized European study comparing MammaPrint with clinical assessment.15 MINDACT has enrolled over 6000 patients, who have been classified into high or low genomic risk by MammaPrint and clinicopathologic risk through Adjuvant! Online. Patients with both genomic and clinical high risks are offered adjuvant chemotherapy; those with both genomic and clinical low risks do not receive chemotherapy; patients with discordant risk are randomized for the decision of adjuvant chemotherapy based on genomic or clinical risk.15 MINDACT is due to complete data collection in 2019.
- Fisher B, Redmond C. Systemic therapy in node-negative patients: updated findings from NSABP clinical trials. National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer Inst Monogr. 1992;(11):105-116.
- Adjuvant Inc. Adjuvant! Online 8.0. www.adjuvantonline.com/index. jsp. Accessed July 23, 2012.
- Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol. 2005;23:2716-2725.
- Mook S, Schmidt MK, Rutgers EJ, et al. Calibration and discriminatory accuracy of prognosis calculation for breast cancer with the online Adjuvant! program: a hospital-based retrospective cohort study. Lancet Oncol. 2009;10:1070-1076.
- Gnant M, Harbeck N, Thomssen C. St. Gallen Consensus Discussion. Breast Care (Basel). 2011;6:136-141.
- National Comprehensive Cancer Network guidelines. www.nccn.org/ professionals/physician_gls/pdf/breast.pdf.
- 7. Pritchard KI, Bergh J, Burstein HJ. Update of the Oxford Overview. www.asco.org/ASCOv2/Home/Education%20&%20Training/Educa tional%20Book/PDF%20Files/2012/zds00112000071.PDF.
- Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-444.
- Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-3734.
- Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826.
- Albain K, Barlow W, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-negative ER-positive breast cancer. Presented at: 30th Annual San Antonio Breast Cancer Symposium, San Antonio, TX. 2007. Abstract LBA10.
- Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26:721-728.
- van ’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530-536.
- van de Vijver MJ, He YD, van ’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999-2009.
- Rutgers E, Piccart-Gebhart MJ, Bogaerts J, et al. The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase. Eur J Cancer. 2011;47:2742-2749.
Genomic Health, Inc, located in Redwood City, California, is a global cancer company founded in 2000. Genomic Health currently offers patients the Oncotype DX Breast Cancer Assay and the Oncotype DX Colon Cancer Assay. Genomic Health maintains that the key to effectively using clinical genomics to improve cancer treatment and [ Read More ]
Key Points Key stakeholders are increasingly considering new measures to protect and advance innovation and investment in diagnostics Efforts are under way to establish more appropriate and least burdensome regulatory policies to address stakeholder concerns specific to in vitro diagnostic tests FDA is concerned with the risk of false-positive and [ Read More ]