Ultralow Risk 70-Gene Signature Is Indicative of Excellent Survival Outcomes in Early-Stage Breast Cancer

Josephine Lopes Cardozo, MD, a PhD candidate

Patients with early-stage breast cancer who have ultralow risk disease indicated by a 70-gene signature demonstrated have an excellent survival prognosis regardless of clinical risk, according to an analysis of patients from the phase 3 MINDACT trial (NCT00433589) presented during the 2021 ASCO Annual Meeting.¹

At a median follow-up of 8.7 years, the 8-year distant metastasis-free interval (DMFI) rate in patients with ultralow-risk disease was 97.0% (95% CI, 95.8%-98.1%) vs 94.5% (95% CI, 93.6%-95.3%) in low-risk patients and 89.2% (95% CI, 87.9%-90.5%) in high-risk patients. The risk of distant metastases or death was significantly lower in ultralow-risk patients vs low-risk patients (Hazard ratio [HR], 0.65; 95% C, 0.45-0.94). Similarly, the risk was lower for low-risk patients, compared with high-risk patients (HR, 2.17; 95% CI, 1.68-2.80). Moreover, the 8-year breast cancer–specific survival (BCSS) rate was 99.6% (95% CI, 99.1%-100%) in patients with ultralow-risk disease, 98.2% (95% CI, 97.7%-98.7%) in those with low-risk disease, and 93.7% (95% CI, 92.6%-94.7%) in those with high-risk disease.

“Our results confirm previously published results of excellent survival in ultralow-risk patients in the largest cohort to date,” presenting author Josephine Lopes Cardozo, MD, a PhD candidate at the Netherlands Cancer Institute and medical fellow at the European Organization for Research and Treatment of Cancer, said during an oral presentation of the data. “As we know, especially in low-risk breast cancers, recurrences occur very late. Longer follow-up will reveal whether the excellent prognosis of ultralow-risk patients continues, as seen in other studies on ultralow-risk [disease].”

Since the 1990s, there has been an increase in the incidence of breast cancer, with a large increase in the incidence of small tumors, and almost no decrease in the incidence of large tumors, according to Lopes Cardozo. However, there has also been an increase in 10-year survival for patients with all stages of breast cancer, with the exception of stage IV disease. This increase in survival rates can be attributed to developments in adjuvant systemic treatment, mammographic screening, and improvements in local and regional treatments.²

The 70-gene signature has demonstrated level 1 clinical utility in identifying patients with a preserved outcome when treated with adjuvant endocrine therapy and no chemotherapy, Lopes Cardozo said. Moreover, the 70-gene signature is able to identify patients who are at a low- or high-risk of distant recurrence within 5 years of breast cancer diagnosis. In 2017, a threshold for ultralow-risk disease was defined as a 100% BCSS rate at 15 years in independent validation cohorts of the 70-gene signature, she explained.^3-5

Two studies have demonstrated that tumors with a low- and ultralow-risk biology, according to the 70-gene signature, are overrepresented in cancers detected through screening. In one study, a cohort of patients were examined prior to the introduction of widespread screening (1984 to 1992) and compared with another cohort of patients who were examined after widespread screening was adopted (2004-2006). Results indicated that there was a significantly higher proportions of patients with low- and ultralow-risk tumors in the screened cohort vs the prior to the widespread introduction of screening cohort.^6,7

Similarly, in Dutch patients who were assessed on the MINDACT trial, a significantly higher rate of low- and ultralow-risk tumors were observed in patients with cancers detected through screening (69%; n = 754) compared with patients whose tumors were found in the intervals between 2 screening rounds (52%; n = 348).

Historically, patients with ultralow-risk tumors, as assessed by the 70-gene signature, have had excellent survival outcomes. In validation cohorts that were used to set the threshold for ultralow-risk tumors, 98% of patients received no adjuvant systemic treatment. Moreover, the 15-year BCSS was 100% for patients with ultralow-risk disease.⁸

Additionally, another prior study analyzed a cohort from the historic STO-3 trial, which examined patients with lymph node–negative breast cancer smaller than 3 cm. Patients were randomized to receive either tamoxifen or no adjuvant systemic treatment. Among patients for whom a 70-gene signature could be performed, 339 received tamoxifen, while 313 received no adjuvant systemic treatment. Results indicated that patients in the cohort with ultralow risk tumors had excellent 20-year BCSS outcomes, with rates of 97% in those who received tamoxifen and 94% in those who received no adjuvant systemic treatment. However, the number of patients with ultralow-risk disease examined on both studies was notably small.

As such, investigators sought to assess survival outcomes in patients with an ultralow-risk tumor biology who were included in the MINDACT trial, as well as examine if the identification of an ultralow-risk patient subgroup by 70-gene signature could help to avoid overtreatment in early-stage breast cancer.

The MINDACT trial enrolled women aged 18 to 70 years old with operable invasive breast cancer and whose tumor size was a maximum of 5 cm. Additionally, patients enrolled on the study could have 0 to 3 positive lymph nodes. Patients with distant metastases were excluded from the trial.

Patients were stratified based on clinical risk by clinical-pathological characteristics and genomic risk based on the 70-gene signature.9 On the study, patients with concordant low-risk stratification received no adjuvant chemotherapy, while those with concordant high-risk stratification did receive chemotherapy. Additionally, the 2 study groups with discordant risk stratification were randomized to follow either the clinical or genomic risk stratification to receive chemotherapy or not, Lopes Cardozo added.

In total, 6693 patients were enrolled on the MINDACT trial. Of those patients, profiling revealed ultralow risk by 70-gene signature in 15% (n = 1000) of patients and 49% (n = 3295) of patients were clinically low risk. Among these patients, approximately 95% presented with hormone receptor (HR)–positive, HER2-negative disease vs 57% of high-risk patients (36%; n = 2398). Additionally, 76% to 85% of patients with low- or ultralow-risk disease received endocrine therapy only or no adjuvant systemic treatment, while 83% of high-risk patients received chemotherapy.

Among the subgroup of patients with ultralow-risk disease, the majority were older than 50 years of age (67%), lymph node-negative (80%), had tumors sized 2 cm or smaller (81%), had grade 1 or 2 disease (96%), and had HR-positive/HER2-negative subtyping (97%). Additionally, 16% of ultralow-risk patients received no adjuvant systemic treatment, 69% received endocrine therapy, and 14% received chemotherapy. Moreover, in terms of clinical risk, 741 of the ultralow risk patients had clinically low-risk tumors, while 259 had clinically high-risk tumors, defined as being larger in size, having a higher grade, and being lymph node positive.

In an assessment of DMFI in genomic ultralow-risk patients by clinical risk, those with clinically low-risk tumors had a slightly higher 8-year DMFI rate of 97.6% (95% CI, 96.4%-98.8%), vs 95.0% (95% CI, 92.3%-97.8%) in those with clinically high-risk tumors.

No statistically significant difference in 8-year BCSS rate was noted among genomic ultralow-risk patients, with the clinically low-risk group achieving a rate of 99.7% (95% CI, 99.3%-100%) and 99.2% (95% CI, 98.0%-100%) in the clinically high-risk group.

Additionally, in patients with ultralow-risk disease who received no adjuvant systemic treatment (n = 157), the 8-year DMFI rate was 97.8% (95% CI, 95.3%-100%), while it was 97.4% (95% CI, 96.1%-98.7%) in those who received endocrine therapy only (n = 685). Lastly, a rate of 94.9% (95% CI, 94.4%-98.7%) was reported in those who received chemotherapy with or without endocrine therapy (n = 144). Notably, 92% of patients who received chemotherapy had clinically high-risk disease.

“The clinical implications of this research are that we can confirm that the 70 gene signature can identify patients with an ultralow risk of recurrence, and that these patients could be candidates for further de-escalation of treatment, thus further reducing overtreatment, and the risk of [adverse] effects,” Lopes Cardozo concluded.

References

1. Cardozo J, Drukker C, Schmidt M, et al. Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial. J Clin Oncol. 2021;39(15):500-500. doi:10.1200/JCO.2021.39.15_suppl.500
2. Autier P, Boniol M, Koechlin A, et al. Effectiveness of and overdiagnosis from mammography screening in the Netherlands: population based study. BMJ. 2017;359:j5224. doi:10.1136/bmj.j5224
3. Piccart M, Veer L, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 2021;22(4):476-488. doi:10.1016/S1470-2045(21)00007-3
4. Veer L, Dai H, Vijver M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-6. doi:10.1038/415530a.
5. Delahaye L, Drukker C, Dreezen C, et al. A breast cancer gene signature for indolent disease. Breast Cancer Res Treat. 2017;164(2):461–466. doi:10.1007/s10549-017-4262-0
6. Esserman L, Shieh Y, Rutgers E, et al. Impact of mammographic screening on the detection of good and poor prognosis breast cancers. Breast Cancer Res Treat. 2011;130(3):725-34. doi:10.1007/s10549-011-1748-z
7. Drukker C, Tinteren H, Schmidt M, et al. Long-term impact of the 70-gene signature on breast cancer outcome. Breast Cancer Res Treat. 2014;143(3):587-92. doi:10.1007/s10549-013-2831-4
8. Esserman L, Yau C, Thompson C, et al. Use of molecular tools to identify patients with indolent breast cancers with ultralow risk over 2 decades. JAMA Oncol. 2017;3(11):1503-1510. doi:10.1001/jamaoncol.2017.1261
9. Cardoso F, Veer L, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016; 375:717-729. doi:10.1056/NEJMoa1602253