By Karuna Jaggar, Former Executive Director and SABCS Guest Writer
Good news for many postmenopausal women with early stage, hormone positive breast cancer. Two new studies presented at the 2020 the San Antonio Breast Cancer Symposium (SABCS) confirm that the majority of these women with low Oncotype DX recurrence scores can skip chemo, even if they have up to three positive lymph nodes.
Thursday morning opened with a late-breaking abstract that showed—once again!—sometimes the best way to help patients is by doing less. Early results from a planned analysis in September 2020 were so promising that the National Cancer Institute (NCI) decided the results needed to be unveiled early and Dr. Kevin Kalinsky kicked off Day 2 with a presentation of the data from the SWOG S1007 study (GS3-00).
The study looked at whether there is any benefit to giving chemotherapy to patients with hormone positive breast cancer, between one to three positive lymph nodes, and a low Oncotype DX Recurrent Score. Two years ago I reported on the TAILORx data presented at the 2018 SABCS, which showed that there is no benefit to giving chemotherapy to the majority of postmenopausal women with hormone positive breast cancer which has not spread to the lymph nodes.
The 21-gene Oncotype DX Recurrence Score, a common genomic test, has been used for more than 15 years to identify which patients with lymph node-negative, hormone-positive, HER2-negative disease can safely skip chemotherapy. Until 2018, doctors didn’t how to treat nearly two thirds of patients with early stage breast cancer with an intermediate recurrence score (between 11-25). The TAILORx study showed that many fewer patients than previously believed benefit from chemotherapy. Those who were shown to benefit were mainly patients with a high Oncotype DX score (26 or higher) and younger women with an intermediate score (16-25).
However, until now, doctors have not known how to treat patients with a low recurrence score (0 to 25 on a scale that goes up to 100) who also have between one and three positive lymph nodes. Because positive lymph nodes are a risk factor for recurrence, physicians have not known whether it is safe to skip chemotherapy for this group of patients.
The SWOG S1007 trial accrued more than 5000 patients with hormone positive, HER2- breast cancer with one to three positive lymph nodes and a low recurrence score. The majority of study participants were white (66%) and one-third were premenopausal. This was not an extremely low risk group: 65% had grade 2 tumors and more than half (57%) had an Oncotype DX recurrence score between 14-25.
The researchers studied the effect of chemotherapy on invasive disease-free survival (IDFF) for these patients and hypothesized that the benefit of chemotherapy would increase as the Oncotype recurrence score increased. But, the researchers reported that recurrence score does not predict the relative benefit of chemotherapy.
Instead, this study showed that chemotherapy did not offer benefit for the postmenopausal group with a recurrence score of 25 or less, even with positive lymph nodes. Overall survival and invasive disease-free survival (IDFS) were not different for the postmenopausal groups who did and didn’t receive chemotherapy. This reassuring study is immediately practice-changing. The majority of postmenopausal women do not need chemotherapy and will do well with hormone therapy alone, with five-year overall survival rates above 96%.
However, premenopausal women did appear to benefit from the addition of chemotherapy in both the intermediate and low recurrent score groups. There was a five-year overall survival benefit of 1.3% for those premenopausal women who received chemotherapy. However, it should be noted that all premenopausal women did very well overall, with high overall survival rates: 97.3% in the hormone therapy only group and 98.6% in the hormone therapy plus chemotherapy group. While there were not many deaths reported in the five year follow up period, there was a 53% relative reduction in deaths by adding chemotherapy.
Researchers also looked at invasive disease-free survival (IDFS) as a primary endpoint and reported an absolute benefit of 5.2% at five years for premenopausal patients who were treated with hormone therapy alone: 89% compared to 94.2% for those who received chemotherapy with hormone therapy. All premenopausal women (in all subgroups) benefitted from the addition of chemotherapy, although the benefit was somewhat less for the group with a lower recurrent score (0-13) compared to an intermediate recurrent score (14-25). The absolute IDFS benefit was 3.9% and 6.2% respectively. The number of positive nodes did not make a difference.
The SWOG findings were reinforced on Friday morning with the presentation of the West German Study Group’s ADAPT trial (GS4-04). The ADAPT trial confirmed the important finding that postmenopausal women with early stage hormone positive breast cancer can skip chemo, even with up to three positive lymph nodes.
Dr. Harbeck presented the hormone portion of the ADAPT study that included 2356 patients, separate from an additional 2500 patients enrolled in another part of the ADAPT study that evaluated nab-paclitaxel and was presented by Dr. Kummel immediately prior. The median age was late 50s, although 30% of participants were premenopausal. Around a quarter of patients had disease found in one to three lymph nodes.
The ADAPT trial asked if one way of identifying who might benefit from chemotherapy in this group might be to look at the impact of a short course of hormone therapy on the cancer. Traditionally, risk has been calculated looking at anatomical factors like tumor size and nodal status—indeed, the question at hand is whether patients with some positive lymph nodes can skip chemotherapy. For the last fifteen years, gene expression at baseline has been used to calculate risk, using tools like Oncotype DX, Mammaprint, Endopredict, and others.
The ADAPT researchers explored whether tumor response—measured with the Ki67 score—to endocrine therapy adds to, or might even replace, other risk assessment tools that guide the use of chemotherapy. Ki-67 is a protein in cells associated with cell proliferation, so a higher score indicates faster growing cancer. Women were treated with a short, three-week course of hormone therapy after which researchers evaluated their Ki67 score, with the goal of identifying who need chemotherapy.
While this is immediately practice changing for postmenopausal women, key questions remain for younger, premenopausal women, who seem to benefit from chemotherapy, regardless of lymph node involvement. Is chemotherapy really worth it, given that they do well overall? The ADAPT trial showed after five years, 94% have not had an invasive recurrence. And, importantly, would ovarian suppression give the same benefit in terms of recurrence without the toxicity of chemotherapy? After all, it’s probably preferable to get a monthly shot rather than use the blunt, and toxic, tool of chemotherapy to indirectly suppress the ovaries as a side effect.
Arguing that the Ki67 response testing complements baseline risk assessment, Dr. Harbeck ended her presentation with a plea: “Please do three week preoperative hormone therapy,” which is cheap and easy, and may possibly inform treatment. Additionally, she suggests the benefits of doing a short course of hormone therapy include that it offers data about tumor response that can encourage women to stick with hormone treatment after surgery.
However, Yale’s Dr. Lajos Pusztai, who was a Discussant (GS4-06) argued that, for now, younger women benefit from chemotherapy, regardless of nodal status. He suggested the hormone test ADAPT is noninformative, given the recurrent score implies the Ki67 score for 75% of pts. Certainly, there will be many oncologists who continue giving this group chemotherapy but there are undoubtedly women who will opt to forgo chemotherapy given the overall good prognosis.
The push to treat is strong and it’s always important to ask: When can we help patients by doing less?
The publicly funded SWOG Cancer Research Network (originally founded in the mid-1950s as the Southwest Oncology Group) is part of the NCI’s National Clinical Trials Network. SWOG is one of the oldest and largest cancer research networks, and includes more than 12,000 people at over 1,000 hospitals, clinics, and cancer centers worldwide.
I think it’s no accident that studies to de-escalate, or reduce, treatment come out of SWOG, and I think this underscores the importance of publicly funded medical research that is not fueled by the incentive of potential patents or future profits. And I want to note that the West German Study Group is openly sharing, for free, the predictive algorithm of endocrine response to short term preoperative hormone therapy that they developed: http://enrep.info. Gotta love openly sharing resources, to save from recreating the wheel.
From cancer to COVID-19, the importance of collaboration and the need for large federal investments in many areas of public health research is clear.