Study: Can tumor tests identify more breast cancer patients who can safely skip chemotherapy?
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What are these studies about?
These studies are about whether tumor tests can identify which breast cancer patients with cancer that has spread to their lymph nodes can safely skip chemotherapy and which patients are most likely to benefit from chemotherapy.
Why are these studies important?
Chemotherapy has long been a part of breast cancer treatment. For many patients, it can have serious and/or long-lasting side effects. These studies looked at how some tumor tests may better identify breast cancer patients who can safely skip chemotherapy (without an increased chance of cancer coming back or recurring) and patients who can benefit from chemotherapy.
Oncotype DX is a type of tumor test. It looks at which genes are active in cancer cells compared to healthy cells. The test assigns scores ranging from 0 to 100. A score of 25 or below suggests that there is a low risk of breast cancer coming back.
Oncotype DX risk scores are used to identify women with hormone-positive, Her2-negative, node-negative breast cancer who would benefit from chemotherapy. The TAILORx study showed that women with this type of early-stage breast cancer and an Oncotype DX recurrence score of 25 or lower did as well on hormone therapy alone as those who were given hormone therapy plus chemotherapy.
The results of TAILORx left an important question unanswered: What is the best way to treat women with early-stage breast cancer that has spread to the lymph nodes? Two recent studies, RxPONDER and ADAPT studied this question in different ways.
Can even more women safely skip chemotherapy?
The RxPONDER study looked at the benefit of chemotherapy in women with early-stage breast cancer that had spread to one to three lymph nodes. About 5,000 patients were randomly assigned to receive hormone therapy alone or hormone therapy plus several months of chemotherapy. Each of these participants had all of the following:
- hormone-positive, Her2-negative breast cancer.
- 1-3 positive lymph nodes.
- an Oncotype Dx score of 25 or less.
Early (five year) results of the RxPONDER study presented at the 2020 San Antonio Breast Cancer Symposium showed that:
- no association was found between recurrence score and chemotherapy benefit. In other words, patients with higher recurrence scores (e.g., up to 25) did not have greater benefit from chemotherapy than those with lower scores (e.g., 4, 5, 6).
- Among premenopausal women, those who received chemotherapy were more likely to be disease-free 5 years later than premenopausal women who received hormone therapy only.
- Among postmenopausal women, there was no difference in disease-free survival whether or not they had chemotherapy.
Based on these findings, many postmenopausal women may be able to safely skip chemotherapy. However, it is important to note that this study showed that there is benefit from combination chemotherapy and hormone therapy for premenopausal women.
Researchers will continue to follow patients for a total of 15 years. This will allow them to collect more data and get a better understanding of how these patients fare over time.
While the results of RxPONDER confirm earlier research that showed chemotherapy benefits premenopausal women, why that is so is unknown. One possible explanation is that chemotherapy can induce menopause, which in turn can starve Hormone-positive breast cancer cells of the estrogen they need to grow.
Additional research is needed to see if premenopausal women who are given menopause-inducing medications plus hormone therapy would respond more like the postmenopausal women in this study who did not benefit from chemotherapy.
The ADAPT study findings
Like the RxPONDER trial, researchers of the ADAPT trial wanted to know whether women with early-stage breast cancer that has spread to the lymph nodes would benefit from chemotherapy.
The ADAPT study looked at whether combining two tests, Oncotype Dx and a tumor marker called Ki-67 could help identify women who are most likely to benefit from chemotherapy and those who may safely skip chemotherapy.
Participants in the ADAPT study had hormone receptor-positive, Her2-negative breast cancer with zero or up to three positive lymph nodes. Unlike the RxPONDER study, all patients in this study received three weeks of hormone therapy after their initial biopsy and before surgery to remove their tumor.
Biopsy tissue was used to get an Oncotype Dx score and a first Ki-67 score. Tumor tissue removed at the time of surgery was used to get a second Ki-67 score.
Researchers used Oncotype DX scores and changes in Ki-67 scores (at biopsy and after surgery) to decide who should receive chemotherapy with hormone therapy and who could receive hormone therapy alone after surgery.
People with Oncotype Dx scores of 12 or higher and Ki-67 scores of 10 percent or higher after three weeks of hormone therapy were given chemotherapy along with hormone therapy after surgery. The results of this group were presented in another presentation and are not included here.
The ADAPT study presents the results for the remaining 2,290 participants who were separated into two groups:
- Those with an Oncotype Dx score of 0 to 11 and 0 to 3 positive lymph nodes.
- Those with an Oncotype Dx score of 12 to 25, 0 to 3 positive lymph nodes and a second Ki-67 score of 10% or less at the time of surgery.
People in these two groups received hormone therapy alone (no chemotherapy).
After five years, in the two groups that received hormone therapy alone:
- the overall survival rate was excellent and similar for both groups.
- survival rates did not differ by age or menopausal status.
- survival rates did not differ for people with 0 to 2 positive lymph nodes.
- people with 3 positive lymph nodes were more likely to have their cancer come back within 5 years (24%) compared to people with 0 positive lymph nodes (3%), 1 positive lymph node (5%) or 2 positive lymph nodes (8%).
This part of the ADAPT study showed that together, a patient’s Oncotype Dx score, Ki-67 scores and lymph node status may help identify women with up to three positive lymph nodes who can safely skip chemotherapy. Based on the results of the ADAPT study the following patients can be safely treated by hormone therapy alone:
- Patients treated with a short course of hormone therapy prior to surgery,0 to 3 positive lymph nodes and Oncotype Dx scores of 0 to 11.
- Patients treated with a short course of hormone therapy prior to surgery, 0 to 2 positive lymph nodes, an Oncotype DX score of 12 to 25 and a Ki-67 tumor score of less than 10% at the time of surgery.
However, patients with hormone receptor-positive, Her2-negative breast cancer, Oncotype Dx scores between 12 to 25 and a Ki-67 score of 10 percent or less with three or more positive lymph nodes may not be good candidates for hormone therapy alone and may benefit from chemotherapy.
Strengths and limitations
- RxPONDER and ADAPT are both very large prospective, randomized studies.
- Follow-up for both studies has been limited. Data will continue to be collected and results may change.
These results are likely to provide more clarity and guidance to doctors who recommend treatment for breast cancer patients who may be able to safely avoid chemotherapy. Many experts believe that national treatment guidelines may change based on the results of these studies.
If you are a premenopausal woman with estrogen receptor-positive, Her2-negative breast cancer, you should speak with your doctor about the possible benefits of chemotherapy. If you are a post-menopausal woman with estrogen-receptor-positive, Her2-negative breast cancer and have zero to three positive lymph nodes, an Oncotype DX test together with Ki-67 tests may help your doctor determine whether or not you will benefit from chemotherapy.
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- What tumor tests have I had?
- How are my tumor test results being used to guide my treatment?
- Can I safely skip chemotherapy?
- With my tumor test results, what are the chances that my cancer will come back?
- NCT03701334. A Trial to Evaluate Efficacy and Safety of Ribociclib with Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer (NATALEE). This study is looking at whether the addition of the drug ribociclib to hormone therapy improves outcomes for women with hormone-positive, HER2-negative early-stage breast cancer.
- NCT04016935. EndoPredict® Extended Endocrine Trial (EXET). This study is looking at the 5 to 10-year outcomes of patients with hormone receptor-positive, HER2-negative early-stage breast cancer tumors with low EndoPredict® (a tumor test used to predict whether cancer will come back after 10 years) scores who did not continue hormone therapy after 5 years.
- NCT04129216. The Effects of Short-term Preoperative Treatment with Hormonal Therapy on Gene Profiles in Breast Cancer. This study is studying how the expression of the Ki-67, estrogen and progesterone receptor genes change after a short course of hormonal therapy before surgery in patients with breast cancer. The goal of this study is to advance personalized treatment for women with breast cancer.
Who covered this study?
Chemotherapy may not be necessary for certain breast cancers, study finds This article rates 5.0 out of 5 stars
Cancer Therapy Advisor
Adjuvant endocrine therapy alone judged suitable for certain breast cancer patients This article rates 4.0 out of 5 stars
RxPONDER: Chemo 'no longer a mandate' for some with breast cancer This article rates 3.5 out of 5 stars
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.
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.
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.
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.
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
- RxPONDER and ADAPT are both very large prospective, randomized studies.
- To date, follow-up for both studies is limited. Data will continue to be collected and results may change.
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.
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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