Recurrence scores spare some patients from chemotherapy

By Neil Osterweil


For many women with breast cancer, definitive surgery or radiation does not end the anxiety sparked by fear of local or distant recurrence. Similar concerns may prompt some clinicians out of an abundance of caution to recommend adjuvant chemotherapy even for patients who are actually at low risk for recurrence.

But in recent years the advent of genetic panels for breast cancer such as the Oncotype DX 21-gene recurrence score and EndoPredict 12 gene molecular score, combined with increased understanding of how to interpret and apply the results, has spared many women from needlessly undergoing chemotherapy with its associated acute and chronic toxicities.


“We’ve been using the Oncotype test in our clinic for more than a decade, and it has been very helpful to us both for getting an assessment of the risk of recurrence and for helping us decide for which hormone receptor–positive breast cancer patients it would be reasonable to add chemotherapy and to select those patients who could avoid it,” Steven Jay Isakoff, MD, PhD, a breast cancer specialist at the Massachusetts General Hospital Cancer Center and assistant professor of medicine at Harvard Medical School, both in Boston, said in an interview.

Kathryn J. Ruddy, MD, MPH, professor of medicine and director of cancer survivorship at the Mayo Clinic College of Medicine in Rochester, Minnesota, said in an interview that with recurrence score testing “we are now able to more precisely inform patients about the potential benefit [or lack thereof] of adjuvant chemotherapy to reduce risk of recurrence of a hormonally sensitive and HER2neu-negative tumor.”

Tailoring results

The phase 3 TAILORx trial showed that with the use of the Oncotype DX 21-gene recurrence score, more than two-thirds of women with hormone receptor–positive, HER2-negative, node-negative early stage breast cancer could safely avoid adjuvant chemotherapy. Results of the trial were reported at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO) and published simultaneously in the New England Journal of Medicine.

TAILORx was designed to address whether chemotherapy added to endocrine therapy would benefit patients with midrange recurrence scores (11 through 25 on the 100-point scale) or, to put it another way, whether they might be harmed if they did not receive adjuvant chemotherapy.


At a median follow-up of 7.5 years, the primary analysis showed that the trial met its primary endpoint: The risk of invasive disease–free survival events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone versus that of counterparts given chemotherapy plus endocrine therapy (hazard ratio, 1.08;
P = .26), reported lead author Joseph A. Sparano, MD, associate director for clinical research at Albert Einstein Cancer Center and Montefiore Health System in New York, as well as vice chair of the ECOG-ACRIN Cancer Research Group.


Dr. Joseph A. Sparano


The study groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, as well as overall survival.

At the 2019 ASCO annual meeting, Dr. Sparano reported results of a secondary analysis of TAILORx showing that combing the 21-gene recurrence score with data on tumor size and histology-based risk stratification improves prediction of disease-free survival, distant recurrence, and for some patients chemotherapy benefit.

“The totality of the data, including TAILORx and the prior prospective validation studies, indicate that assessment of genomic risk with the 21-gene recurrence score provides complementary prognostic information to pathologic features, and is also predictive of a large chemotherapy benefit if the recurrence score is greater than 25, or lack thereof if 25 or lower,” he said.

Dr. Jane E. Brock

Nodal status considered

Results from a large national cohort study also suggested that patients with limited axillary node involvement might still be safely spared from chemotherapy. An analysis of data on 30,864 grade 3 breast cancers registered in the National Cancer Database found that 30% of pN0 and 27.1% of pN1 hormone receptor–positive, HER2-negative cancers had low recurrence scores, which suggests little or no benefit from adding chemotherapy.

“To our knowledge, these findings represent the largest analysis to date of the potential impact of recurrence score on the outcomes and management of grade 3 tumors, and suggest that the assumption that all pT1c/2 pN0/1, [estrogen receptor–positive] histopathologic grade 3 tumors are high risk and will consequently benefit from adjuvant chemotherapy may be unmerited,” wrote Jane E. Brock, MD, PhD, from the Dana-Farber Cancer Institute, Boston, and Harvard Medical School and colleagues in JCO Precision Oncology.

The question of whether patients with low-volume, node-positive disease (1-3 nodes) could safely avoid chemotherapy is currently being explored in the RxPONDERtrial.

Dr. Isakoff said that he and his colleagues are eagerly awaiting results from this trial.

“I think the guiding principal in general is that, if we’re on the fence about chemotherapy and additional information would help us to make that decision, then the Oncotype test can be useful in that setting, and increasingly for limited node-positive patients, we’re finding that question comes up, and we consider using it,” he said.

12-gene test

A different clinicomolecular test, the EndoPredict (EPclin) 12-gene clinicomolecular assay score, can also provide clinicians with guidance on the expected absolute benefit from adjuvant chemotherapy, in addition to prognostic information for patients with ER-positive, HER2-negative early-stage breast cancer, according to William Gradishar, MD, professor of breast oncology and medicine and chief of the division of hematology/oncology at the Robert H. Lurie Comprehensive Cancer at Northwestern University in Chicago, and colleagues.

As they reported in JCO Precision Oncology the investigators created a mathematical model to determine the average relative benefit of chemotherapy for reducing distant recurrence using a published meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, and they estimated absolute chemotherapy benefit differences across a range of interaction strengths between relative chemotherapy benefit and the EPclin score. Finally, they calculated average absolute benefit for patients with high and low EPclin scores using the distribution of scores in 2,185 samples tested by Myriad Genetics, maker of the assay.

They found that the average expected absolute benefit of chemotherapy treatment for patients with a low EPclin score was 1.8% assuming no interaction between prognostic factors and chemotherapy benefit and 1.5% for maximal interaction, which suggests no significant added benefit from chemotherapy.

In contrast, for patients with a high EPclin score, the absolute benefit assuming no interaction was 5.3% and the benefit assuming maximal interaction was 7.3%.

In the clinic

Dr. Ruddy said that the patients most likely to benefit from recurrence score testing are those with grade 2 tumors with no or minimal nodal burden, who have tumors with widely varying degrees of chemosensitivity.

“But there are also plenty of grade 1 and grade 3 tumors that surprise us; in other words, are found by a genomic test to be more or less chemosensitive than we expect, and we also sometimes are able to use genomic testing to avoid chemotherapy administration in patients with multinode-positive disease,” she said.

“My threshold for recommending chemotherapy is affected by the individual patient’s situation [because stage, age, and comorbidities impact the risk-benefit ratio]. For example, for a patient who is 70 years old with a small tumor that did not involve any axillary nodes, I would likely not recommend chemotherapy with an OncotypeDx Recurrence Score under 26, or perhaps even 30. On the other hand, I might offer chemotherapy to a 35-year-old with a 4-centimeter tumor that had spread to an axillary node even with an OncotypeDx Recurrence Score of 22,” she added.

Dr. Isakoff noted that the Oncotype test provides both prognostic and predictive information, and “even if the test score predicts a relatively low benefit from chemotherapy, if the clinical risk is high enough that there’s a high chance of recurrence, then even a small chemotherapy benefit might be worthwhile.”

“So it’s really looking at a lot of features together: the size, the grade, and certainly the patients’ age. Many of us have a higher threshold for including chemotherapy in older patients and a higher threshold to eliminate chemotherapy in the node-positive population,” he said.

The estimated primary completion date of the RxPONDER trial is February 2022. Stay tuned.

Dr. Isakoff disclosed a prior consulting or advisory role for Myriad Genetics. Dr. Ruddy reported having no relevant disclosures.


Cost savings predicted

The additional costs of routine testing with genetic panels will likely be offset by cost savings in the first year after a breast cancer diagnosis, Angela Mariotto, PhD, and colleagues concluded in a study published in JNCI: Journal of the National Cancer Institute.

They used data from the Surveillance, Epidemiology and End Results (SEER), SEER-Medicare, and SEER–Genomic Health datasets to assess how expected changes in practice after the trial might affect costs. They estimated Oncotype DX testing and chemotherapy rates and mean initial costs in 2018 dollars in the pre-TAILORx period (2010-2015) and post-TAILORx period (2018), assuming all women in the latter period received the test and score-suggested therapy.

Going from the pretrial period to the posttrial period, Oncotype DX testing costs were projected to increase from $115 million to $231 million, but chemotherapy use was projected to decrease from 25% to 17%. Mean total initial costs of care fell from $2.816 billion in the pretrial period to $2.766 billion in the posttrial period, for a net savings of $49 million (a 1.8% decrease).

Findings were similar in a variety of sensitivity scenarios entailing alternative compliance with testing, score-suggested treatment, and estimation methods. The only exception was the unlikely scenario in which all women aged 50 years or younger having a recurrence score of 16-25 opted to receive chemotherapy, wherein initial care costs could increase by $105 million (a 4% increase).