The New England journal of medicine 2016-08-25
70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.
Abstract
Background
The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy.
Methods
In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher.
Results
A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease.
Conclusions
Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).
Related Questions
What factors do you take into account when deciding which gene expression assay to utilize when making adjuvant treatment decisions in patients with non-metastatic breast cancer?
Oncotype DX has been validated in multiple large prospective trials and has demonstrated predictive value, while MammaPrint has not been validated to be predictive for chemotherapy benefit but only identifies low-risk biology. Oncotype DX has been validated in node-negative and 1–3 node-positive dis...
Would a low genomic MammaPrint score deter you from offering adjuvant chemotherapy to a premenopausal woman with HR+ pT3N0 breast cancer?
The MINDACT trial only included 11.6% T3 patients. And in MINDACT’s updated analysis, in women ≤50 years old with high clinical risk, there was about a 5% absolute difference in DMFS at 8 years, favoring chemotherapy even if they have low genomic risk. Of course, there is debate about whether chemot...
How do you approach ovarian function suppression in premenopausal women with HR+/HER2-, node negative breast cancer and intermediate OncoType dx scores (11-25) who received chemotherapy?
The SOFT/TEXT data showed that the patients who benefited from ovarian suppression + endocrine therapy were those who were <35 years old or those who had prior chemotherapy (essentially those patients who were deemed to have high risk disease). The TAILORx study demonstrated that patients with recur...
What is your approach for adjuvant therapy when a patient has discordant Oncotype RS (e.g. <20) and MammaPrint (e.g. high risk Luminal B) in node negative HR+Her2- breast cancer?
In terms of the Mammprint, the question here is whether the patient is at low clinical risk or high clinical risk. A stage 1 patient is likely to be considered low clinical risk. In these patients, the MINDACT trial showed that Mammaprint was not able to accurately predict the benefit of chemotherap...
For anatomic stage III ER/PR+ breast cancer treated upfront with surgery, how do you decide which adjuvant chemotherapy to offer?
Anatomic stage III breast cancer includes different clinical scenarios ranging from a tumor over 5cm with 1-3 + lymph nodes, tumors with 4 or more + lymph nodes, tumors with chest wall/skin invasion, and inflammatory breast cancer. For the first scenario, a T3N1 post menopausal female with an Oncoty...
How would you council a woman in her 50s with Stage I HR+/HER2- breast cancer with a high risk Mammaprint but intermediate OncotypeDx regarding adjuvant chemotherapy?
This is a challenging question to address without more details. The first question is why were two different assays run on the tumor? Also, in the context of the TAILORx data which demonstrated a lack of benefit from chemotherapy for postmenopausal women with Oncotype DX recurrence scores 25 or less...
Would you offer adjuvant chemotherapy for 1-3 node positive HR+, HER2 negative breast cancer with Mammaprint low risk to a young, pre-menopausal patient?
Until we have the results from the RxPONDER trial (which used Oncotype, not Mammaprint, but addresses this question more directly than MINDACT), we cannot rule out a potential benefit from adjuvant chemotherapy in node-positive patients like these, and thus, I would offer it while saying that the be...
How would you approach adjuvant systemic therapy for a pT3N0(i+) HR+/HER2 negative breast cancer with an intermediate oncotype in a post-menopausal woman?
This is a great question that I ponder a lot. I've asked countless colleagues informally "what's the largest tumor you'll trust oncotype on"? The only true “prediction” data we have comes from the original B-20 trial, which included T3 tumors. Although the publication only breaks out tumor size as >...
For ER+ breast cancers that are clinical Stage IIB (T2N1) nearing locally advanced stages, what criteria do you use to determine if you would offer neoadjuvant chemotherapy?
This is an interesting question. Assuming this is regarding ER positive but HER2 negative tumors, the factors I would consider that would favor the decision to use upfront chemotherapy are the following: 1. Tumors that are grade 3 or high Ki-67 2. Low ER positive tumors 3. Younger, premenopausal wom...
Can you use Oncotype for determining adjuvant therapy in a young, premenopausal woman with multifocal HR+ breast cancer s/p mastectomy with 2 positive lymph nodes?
There are no data yet that I am aware of (retrospective or prospective) for the use of Oncotype 21 gene assay to make treatment decisions in premenopausal women with node positive, estrogen receptor positive early stage breast cancer. The prospective RxPONDER trial will hopefully provide data on the...
What chemotherapy regimen do you prefer for postmenopausal women with T1 ER positive tumors with 1 positive LN?
For T1N1M0 ER positive tumors, I first do a Mammaprint. In MINDACT, Mammaprint low risk ER + N+ (up to three nodes) tumors had no improvement in 5 year DDFS (still about 94-95%) with the addition of chemotherapy to endocrine therapy.If the woman had a high risk Mammaprint, I would give AC x 4 follow...
Do you use gene expression profiling for premenopausal women with hormone receptor positive breast cancer with 1-3 positive lymph nodes?
I do use gene expression profiling in premenopausal women with 1-3 nodes positive.Premenopausal women represented 33% of all women in MINDACT (NEJM, 2016) (about 2100, a substantial number) and more than half of these premenopausal women had low genomic risk (and therefore a median 5 year distant di...
Do you send Oncotype in patients with ER/PR+ breast cancer and micrometastasis in one sentinel node?
I do send a Mammaprint, as the MINDACT trial (NEJM 2016) demonstrated that women with ER positive breast cancer and 0-3 LN with a low risk profile had a 94.5% 5 year distant disease free survival with endocrine therapy alone. If high risk, I'd offer AC x 4, taxol x 12, which is my standard regimen f...
For early-stage, HR+ Her2- breast cancers, when do you use OncotypeDx v. Mammaprint?
The reason to use any multiparameter assay is to determine which patients need chemo and which don't. To say that another way - it is about the predictive ability, not the prognostic ability. Until very recently, Mammaprint only had prognostic data so I always used Oncotype. The MINDACT trial recent...
Do you routinely send Oncotype Dx on ER positive tumors with node positive disease?
I believe that the intrinsic biology of the tumor is more important than the lymph node status in determining prognosis and potential chemotherapy benefit. Given this, I do use molecular assays for node positive disease with caution. Based on a 2010 Lancet Oncology paper in which tissue blocks from ...
Would you use MammaPrint in patients with triple-negative or HER2-positive breast cancer based on the results from the MINDACT trial?
The MINDACT data from the 2016 NEJM article has a lot of detail, in particular Table 1, which gives the number of subjects in each risk group sorted by clinicopathologic features. There were 638 Her2 positive subjects out of 6693 total, or 9.5%. Of these, 501 (7.5% of total) were ER positive and Her...
How do you approach patients with low ER positive (1 - 9%) breast cancer?
The EBCTCG meta-analysis on adjuvant tamoxifen found benefit with tamoxifen use across all subgroups of ER expression, including the low expressors (1-9%). The absolute benefit of tamoxifen may not be significantly high. In my practice, I do offer anti-estrogen therapy in such a setting, but have a ...
How are you planning to use Mammaprint for the management of locally advanced ER+ breast cancer at clinical high risk of recurrence based on size and up to 3 lymph nodes?
This is an interesting question. I am going to use Mammaprint in the adjuvant setting for patients with high risk of recurrence for tumors of any size and for 0-3 LN positive. These were the criteria used in the MINDACT study, and the 5 year distant DFS in these patients was 95% with endocrine thera...