Study: Can tumor tests identify more breast cancer patients who can safely skip chemotherapy?

IN-DEPTH REVIEW OF RESEARCH

Study background

Historically, most patients with breast cancer who were hormone receptor-positive and node-negative received chemotherapy, but many may not have benefited from it. Tumor tests that may help predict an individual’s risk of recurrence and indicate those who would most benefit from chemotherapy are now available.

Oncotype DX is a test to predict whether chemotherapy will benefit a patient with hormone receptor-positive breast cancer. Recurrence scores are based on RNA expression of 21 genes. Recurrence scores range from 0 to 100.

The results of the TAILORx trial, the largest breast cancer treatment trial ever conducted, suggest that the Oncotype DX tumor test could identify up to 85 percent of women with early breast cancer who can forego adjuvant chemotherapy. This applies especially to women older than 50 who have a recurrence score of 25 or less and women 50 years of age or younger with a recurrence score of 15 or less. This trial was previously discussed in an XRAY review here.

While the TAILORx trial was groundbreaking, more studies were needed to clarify which women need more of some therapies and less of others. For example, it was uncertain which if any women with early-stage node-positive breast cancer could safely forgo chemotherapy.

Two studies presented at the 2020 San Antonio Breast Cancer Symposium attempted to answer this important question.

Researchers of these studies wanted to know if tumor tests could be used to identify more women who can safely forgo chemotherapy.  Specifically, are there women with hormone receptor-positive, Her2-negative breast cancer who are candidates for chemotherapy by standard criteria who can safely be treated with hormone therapy alone?
 

The RxPONDER trial

Populations looked at in this study

RxPONDER is a prospective, randomized trial of hormone therapy versus chemotherapy combined with hormone therapy in women with one t three positive lymph nodes and an Oncotype Dx score below 25. Eligible participants were women over 18 years of age with hormone receptor-positive, HER2-negative breast cancer with one to three positive lymph nodes.

Study design

A total of 9,383 women with HR-positive, Her2-negative breast cancer and one to three positive lymph nodes were screened to identify those with Oncotype Dx recurrences scores of 25 or less. Among those identified, 5,083 patients were randomly assigned to receive hormone therapy alone or hormone therapy plus several months of intravenous chemotherapy with taxane and/or anthracyclines. These chemotherapy drugs are considered to be standard treatments for this type of cancer.

The primary goal of the study was to determine the effect of chemotherapy on disease-free survival and whether the effect depended on Oncotype Dx scores. All women were monitored for about five years to assess invasive disease-free survival, or IDFS, a measure that counts which patients develop cancer that spreads outside of the breast, develop a new tumor inside a breast or die from any cause. Overall survival was a secondary assessment.

Study findings

As a data and safety monitoring committee began reviewing the trial results, they noticed a surprising pattern—one that was clear enough for them to recommend that the findings be reported publicly before the final analysis was complete.

Data from 5,015 participants were used in the early five-year analysis.

• Among postmenopausal women:
  • The five-year disease-free survival rate was 91.6% for the chemotherapy-plus-hormone therapy group and 91.9% for the hormone therapy-only group.   
• Among premenopausal women:
  • The five-year disease-free survival rate was 94.2% for the chemotherapy-and-hormone therapy group, compared to 89.0% for the hormone therapy-only group.
  • Premenopausal women also had an overall survival benefit from chemotherapy.
    • At five years, the overall survival rate was 98.6% for those receiving chemotherapy plus hormone therapy and 97.3% for women in the hormone therapy-only group.

The ADAPT trial

Populations looked at in this study

Among the 5,625 registered participants, 2,290 women with hormone receptor-positive, Her2-negative breast cancer who were candidates for chemotherapy by standard criteria were studied in the ADAPT hormone therapy arm.

Study design

The ADAPT trial looked at combining two tumor scores, Oncotype Dx and a tumor marker called Ki-67, to see if combining these scores could identify women with up to three positive lymph nodes who were most likely to benefit from chemotherapy. The study was done as follows:

• All patients had a biopsy.
• Biopsy tissued was tested by Oncotype Dx to generate a recurrence score and tested to see what percentage of tumor cells had the Ki-67 tumor marker.
• All patients had a short course (about 3 weeks) of hormone therapy before surgery.
• After surgery, patients’ tumors were again scored for Ki-67.
  • If the second Ki67 score was less than 10% (less than 10% of tumor cells had the Ki-67 tumor marker), the researchers used that as an indication that patients were responding to hormone therapy.
• Researchers grouped patients by Oncotype Dx and their second Ki-67 score. The two groups that received hormone therapy alone were:
  • those who had an Oncotype Dx score of 0 to 11 (868 participants) and had a Ki-67 score of less than 10% at the time of surgery.
  • those who had an Oncotype Dx score of 12 to 25 (1,422 participants) and had a Ki-67 score of less than 10% at the time of surgery.

• Women with Oncotype Dx scores of 12 or higher and Ki67 scores of 10% or higher after 3 weeks of hormone therapy were given chemotherapy with hormone therapy after surgery.  The results of this group were presented in another presentation and are not included here.

Study findings

After 5 years:

• The overall survival rate was excellent and similar for both groups.
  • Patients with Oncotype Dx scores of 0 to 11 had a 5-year survival rate of 98%.
  • Patients with Oncotype Dx scores of 12 to 25 who were responding to hormone therapy had a 5-year survival rate of 97%.

• Survival rates did not differ by subgroup such as age or how many positive lymph nodes a patient had except for one subgroup of women with 3 positive lymph nodes.
  • Patients in this subgroup with recurrence scores of 12 to 25 who responded to pre-surgery hormone therapy had a significantly lower 5-year disease-free survival rate of 76% compared to patients with no positive lymph nodes (97%), 1 positive lymph node (95%) or 2 positive lymph nodes (92%).

• The ADAPT study showed that regardless of age, the following patients can be safely treated by hormone therapy alone:
  • Patients with 0 to 3 positive lymph nodes and Oncotype Dx scores of 0 to 11.
  • Patients with 0 to 2 positive lymph nodes and Oncotype DX scores of 12 to 25 who are responding to hormone therapy based on Ki-67 tumor scores of 10% or lower.

• The ADAPT study also suggests that patients with 3 positive lymph nodes who had Oncotype Dx scores of 12 to 25 and responded to hormone therapy based on Ki-67 tumor scores may not be good candidates for hormone therapy alone and may benefit from chemotherapy.

Looking at Oncotype Dx scores score together with Ki-67 scores may help identify women who can safely skip chemotherapy.

Why are study results different?

The results of RxPONDER and the ADAPT studies seem to be different based on menopausal status and the number of positive lymph nodes.

• RxPONDER showed that postmenopausal women with up to 3 positive lymph nodes do not benefit from chemotherapy.
• ADAPT showed that regardless of menopausal status, women with 3 positive lymph nodes likely benefit from chemotherapy.

These differences are likely due to how the two studies were conducted. Both studies looked at Oncotype Dx scores in patients with early breast cancer and 0 to 3 positive lymph nodes.

However, patients in the ADAPT study had:

• a short course of hormone therapy before surgery (patients in the RxPONDER study did not).
• a Ki-67 tumor score at biopsy and at surgery.  This score was used to identify patients for whom hormone therapy seemed to be working. (Ki-67 scores were not used in RxPONDER so researchers did not identify which patients might not respond to hormone therapy.)

Strengths and limitations

Strengths

• RxPONDER and ADAPT are both very large prospective, randomized studies. 

Limitations

• To date, follow-up for both studies is limited.  Data will continue to be collected and results may change.

Context

The side effects of chemotherapy can be devastating.  While some resolve quickly, others may last months, years or even a lifetime. The results of the RxPONDER and ADAPT studies are likely to be useful in the clinic and expand the number of patients who can safely forgo chemotherapy.

Conclusions

These studies represent important steps towards the goal of more personalized medicine. By matching patients to the treatments that will likely benefit them, doctors can also identify patients which are unlikely to benefit from treatments.

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posted 3/4/21