Personalized Medicine Progressing in Premenopausal Breast Cancer

Joyce A. O’Shaughnessy, MD

Eight-year follow-up findings from the TEXT and SOFT trials provided considerable insight into the use of adjuvant endocrine therapy for women with premenopausal hormone receptor (HR)—positive breast cancer, said Joyce A. O’Shaughnessy, MD. However, more follow-up is needed to fully understand how stopping therapy at 5 years will impact disease-free survival (DFS).

The addition of ovarian suppression to adjuvant tamoxifen significantly improved the rates of DFS and overall survival versus tamoxifen alone at 8 years, according to results from the joint analysis. The risk of recurrence was further reduced when exemestane was used in combination with ovarian suppression. Although the analysis confirmed that women with high-risk features require an LHRH inhibitor plus an aromatase inhibitor (AI), results of a subset analysis revealed that tamoxifen alone may be sufficient for women with low-risk disease.

“We're beginning to be able to personalize therapy for premenopausal women,” said O’Shaughnessy, co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center, Texas Oncology. “This is critically important because endocrine therapy for premenopausal estrogen receptor (ER)—positive women is by far the most important therapy.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, O’Shaughnessy, also chair of The US Oncology Network and a 2016 Giant of Cancer Care^® in Community Outreach, discussed the clinical implications of the TEXT and SOFT trials for women with premenopausal HR-positive, HER2-negative breast cancer, as well as unanswered questions that remain with adjuvant endocrine therapy.

OncLive: What are the clinical implications of the TEXT and SOFT trials?

O'Shaughnessy: Based on the 8-year follow-up from the TEXT and SOFT trials, the most important practical point with regard to endocrine therapy for premenopausal women is that women who have very low-risk indolent disease who are not going to receive chemotherapy may do fine with tamoxifen alone provided that they're not too young. These are women under the age of 35 or even 40. Women over the age of 40 with very indolent, low-risk disease are also appropriate candidates for tamoxifen.

Conversely, the more high-risk features younger women have, the greater the benefit of an AI plus an LHRH agonist. These features include progesterone receptor (PR) negativity, large grade 3 cancers, highly proliferative disease, and node-positive disease. Getting therapy right and utilizing an AI plus an LHRH agonist for the patient with high-risk features is critically important as there is up to a 15% absolute benefit in distant DFS.

Are there outliers within these patient subsets?

One of the groups that we worry about are the women who are overweight, particularly the obese patients. There are some data that suggest it's harder to suppress ovarian estrogen levels as thoroughly with LHRH agonists plus an AI in an obese woman compared with a woman of normal weight. That's a little bit of a concern, particularly if she has high-risk features. The data show that a woman with a highly aggressive and proliferative grade 3 PR-negative breast cancer is better off getting an AI plus an LHRH agonist.

However, if she's substantially overweight or obese, we have to monitor ultrasensitive estradiol levels and see if they can be suppressed to less than 10 pg/mL. The question is whether she is better off having her ovaries removed with a bilateral salpingo-oophorectomy; that may be the case. In the ABCSG-12 trial, the investigators showed that overweight and obese women didn't do as well with an LHRH agonist plus an AI compared with a woman of normal weight with the AI compared with tamoxifen alone. That's an area of some controversy; we want to be aware of that and monitor the ultrasensitive estradiol levels in substantially overweight or obese women.

How do patients generally tolerate the combination of an AI and LHRH agonist?

In the SOFT and TEXT trials, about 20% of premenopausal women did not finish their 5 years of therapy. There are considerable adverse events (AEs) for these younger women with regard to menopausal symptoms, dyspareunia, lack of libido, arthralgias, and fatigue.

The other area of concern is the [schedule of LHRH agonists]. In the SOFT and TEXT trials, the LHRH agonist was given every 4 weeks, and it’s very difficult to come in every 4 weeks for 5 years. If the ovaries start breaking through because the LHRH agonist is gone, particularly if a woman is on an AI, the AIs can stimulate ovarian function if the ovaries are not suppressed with an LHRH agonist.

Although investigators working on the clinical trials gave patients the LHRH agonist every 4 weeks, I tend to use a longer depot formulation. I don't really trust it to last for 12 weeks, so I usually will go 10 weeks; that gives the woman a little bit of wiggle room if she's a week late. To be on the safe side, I check the ultrasensitive estradiol levels when she comes in and make sure that her ovaries are still suppressed.

I'm concerned that every 4 weeks is difficult for women to religiously get in. If women are a little bit older, in their mid- to late-40s, it's easier for them to go ahead and have an oophorectomy. It's the younger women, particularly those who are under 40 or in their early 40s [that are of concern]. Right now, the standard of care is 5 years of an LHRH agonist and stop, so that they can regain ovarian function, depending on how much chemotherapy they have had, etc. Adherence to therapy for the full 5 years is critically important to a woman's outcome, but unfortunately, some women can't put up with the AEs.

Do the presence of certain mutations impact these decisions?

Women who have a germline mutation in BRCA1/2, PALB2, RAD51, etc., are at risk for ovarian cancer and will end up needing their ovaries removed anyway. That's somewhat easier for them because they really don't need the LHRH agonist. Aside from that, sometimes women with ER-positive breast cancer and a BRCA1 mutation have more aggressive breast cancers; if it’s not as strongly ER-positive, they would certainly need an AI. Patients with BRCA2 mutations can go either way; their disease can be quite indolent, or it can be more aggressive. That’s not particularly discriminating. The question is really whether they need to remove their ovaries anyway, due to a germline mutation that increases their risk.

What research questions still need to be addressed?

We're waiting for additional follow-up on what happens over time when these premenopausal women stop the LHRH agonist at 5 years. If they're young enough, they have ovarian function recovery. The National Comprehensive Cancer Network and ASCO guidelines suggest that such women go on to 5 years of tamoxifen, so they recommend 10 years of endocrine therapy if patients are not postmenopausal. If they stop the LHRH agonist, they have to stop the AI too, but what happens?

Right now, we have 8 years of follow-up—so these women have been off therapy for 3 years. Thus far, it's okay; it doesn't look like there is a big decrease in DFS. It doesn't look like there is an uptick in recurrences, but it's still early. There can be a carry-over effect for 3 to 5 years. Fortunately, we're going to get longer follow-up from the SOFT and TEXT trials. These women are being prospectively followed for a very long period of time. That's the number one thing we struggle with in practice because we need more follow-up.

Francis PA, Pagani O, Fleming GF, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Eng J Med. 2018;379:122-137. doi: 10.1056/NEJMoa1803164.