HR+ Breast Cancer: Impact of RxPONDER on Clinical Practice

Lajos Pusztai, MD, PhD: The important question that the RxPONDER results pose is whether premenopausal woman with 1 to 3 positive nodes, who seem to have benefited from adjuvant chemotherapy regardless of the recurrence score, even below 25, should actually get a recurrence score. Since we know that it doesn’t matter what their recurrence score is, they still benefit from chemotherapy. I think it is a fair conclusion from the study that most premenopausal woman, with lymph node-positive disease that’s only 1 to 3 nodes, should safely decide to go along with chemotherapy. There is evidence that it could improve their survival: both the invasive disease-free and distant, recurrence-free survival. However, in some instances, it might be helpful to get a recurrence score, even in this population. What are these instances? For example, patients who want to see the absolute predicted benefit from chemotherapy, because of the potential risks of chemotherapy, or patient reluctance to accept it, or comorbid illnesses. Seeing the actual risk of recurrence as a predictive number, to help show the improvement chemotherapy would add, would empower a person to make a personalized decision based on their own value system, about the risks and the benefits of the chemotherapy. The value of the recurrence score, in this instance, is really providing an objective metric on which the patient could base a decision. However, I also think that for many premenopausal women, the test is not that helpful.

Priyanka Sharma, MD: I think the question comes down to how confident we are, in every situation, that the number of positive nodes is no more than 3, because the eligibility criteria for RxPONDER was 1 to 3 positive nodes. And the treatment paradigm for managing axillae has changed based on well done surgical trials. These surgical trials demonstrate that patients who have low-burden axillary disease can forego further axillary dissection because the chances of finding additional lymph node positivity is low and doesn’t negatively impact their survival. In SWOG-1007, about one-third of patients had sentinel lymph node biopsy only. In my practice, I feel comfortable in making my decisions based on sentinel lymph node biopsy only if the patient had 1 or 2 positive nodes and they fulfill the criteria for avoidance of axillary dissection. I don’t feel I need to recommend an axillary dissection for all postmenopausal women with node-positive disease.

Lajos Pusztai, MD, PhD: The result seen in the TAILORx and RxPONDER studies is highly consistent. Remember in TAILORx, the group that benefited was the younger woman, less than 50 years old. In RxPONDER, it was the premenopausal women, the majority of which were also less than 50. If the chemotherapy is beneficial, it could be for 2 reasons. One is the cytotoxic effect of chemotherapy on micrometastatic disease. Basically, the chemotherapy kills the micrometastatic cells through its cytotoxicity. The other well-recognized effect of chemotherapy is on the ovarian function of younger women. Chemotherapy causes ovarian function suppression in perimenopausal women, or women in their late 40s. The ovarian suppression is oftentimes permanent.They undergo a premature chemotherapy-induced menopause. In younger women, especially in their early 30s, chemotherapy-induced menopause is oftentimes reversible and only lasts for a year or two. We also know that in younger women, in the combined moderated hormonal therapy, there is ovarian suppression plus tamoxifen, which is the drug that was given in most of the patients in RxPONDER because, remember, this study was conducted between 2010 and 2017. Tamoxifen with ovarian suppression is better than tamoxifen alone. Ovarian suppression can be induced by Lupron, or leuprolide, or GnRH [gonadotropin-releasing hormone] analogues, but it also could be induced by chemotherapy. The question is, does the chemotherapy-induced ovarian function, or the cytotoxicity of chemotherapy, drive the benefit in these 2 trials? This is unknown. Of course, this is a very important question because chemotherapy is more toxic than ovarian suppression with another drug, such as a GnRH analogue. My opinion is that both effects of chemotherapy probably contribute to the benefit. It’s not necessarily a mutually exclusive question of either this or that. I think both effects contribute, and the relative contribution may vary by age. I think, in younger women in their 30s, it’s the cytotoxic effect that is probably more important. In older women, or perimenopausal women, who are just 1 or 2 years away from their natural menopause, the chemotherapy-induced menopause may be an important driver. However, we don’t really know this, and there are additional studies that are planned behind the RxPONDER study, where we want to get serum markers to try to get more precise answers to this question. But ultimately, new clinical trials will be required to really settle this question.

Priyanka Sharma, MD: How should we take these results in women with 4 or more positive nodes, especially the postmenopausal women? Can we take the results from SWOG-1007 and apply it to those women?

We do not have data from trials on this question since SWOG-1007 only included patients with N1 disease. I think this is a question that is being answered in another large trial, OPTIMA, which is enrolling patients with a higher clinical risk disease. Currently, I do not take these results to patients with N2 or higher disease. If they have higher clinical risk disease, even if they’re postmenopausal, I am recommending chemotherapy. I’m not translating this to higher nodal disease in my practice yet. I think we need to await more data on that.

Lajos Pusztai, MD, PhD: The question is whether these findings have any relevance in the neoadjuvant setting. Remember, both TAILORx and RxPONDER are adjuvant trials. Patients had their tumor removed, and then their pathological assessment shortly after, for positive or negative disease, with the precise understanding of how many nodes are involved and how big the tumor was. However, these results do have some implications for the use of neoadjuvant chemotherapy in early stage breast cancer. Many studies have shown that pathological complete eradication of tumors almost never happens in ER-positive disease that has a recurrence score of less than 25. This goes along with the observation from both of these studies that by and large, a recurrence score below 25 is not associated with significant chemotherapy sensitivity. I think neoadjuvant chemotherapy has some limited value in ER-positive disease. It certainly can downstage the tumor, or shrink the cancer, and make the operation easier. Or an inoperable patient could be converted to operable by neoadjuvant chemotherapy. However, complete pathological eradication of the cancer is very rare.

I think neoadjuvant chemotherapy works best in the very high recurrence score spectrum, recurrence scores above 30. An alternative to neoadjuvant chemotherapy in ER-positive patients is neoadjuvant endocrine therapy. Endocrine therapy can also accomplish many of the same benefits that chemotherapy would in this setting, such as downstaging the tumor, reducing the size of the cancer. I think for patients who have a lower recurrence score on the core biopsy, neoadjuvant endocrine therapy is probably a better choice than neoadjuvant chemotherapy. On the other hand, women with a high recurrence score who would require chemotherapy anyway, neoadjuvant chemotherapy could be meaningful in the sense that it makes their surgery smaller because the cancer shrinks. Ultimately, they would require the same chemotherapy anyway postoperatively, because of the high recurrence score.

Transcript Edited for Clarity