Case 1

Dr. Matthew Goetz:

Hello, my name is Dr. Matthew Goetz and welcome to a new installment in the JNCCN Video Roundtable series. I’m Professor of Oncology and Pharmacology at the Mayo Clinic. And joining me today are two of my colleagues, Dr. Ann Partridge from Dana-Farber, as well as Dr. Katie Ruddy here from Mayo Clinic. I’m going to let each of them introduce themselves. So, Dr. Partridge?

Dr. Ann Partridge:

Thank you Matt. Can we go by first names here?

Dr. Matthew Goetz:

Absolutely.

Dr. Ann Partridge:

All right, good. I’m Ann Partridge. I’m a breast medical oncologist at Dana-Farber Cancer Institute where I also focus on breast cancer in young women, which is particularly relevant for our discussion today as well as cancer survivorship. Katie?

Dr. Katie Ruddy:

Thanks Ann and Matt. Hi, I’m Katie Ruddy. I’m at Mayo Clinic Rochester with Matt and also am very much engaged in research and clinical care related to young women with breast cancer.

Dr. Matthew Goetz:

Thank you very much Ann and Katie. So today as mentioned, we’ll be discussing the management of premenopausal as well as perimenopausal patients who carry a diagnosis of early breast cancer. We will also have a case that illustrates the importance of ovarian function suppression in advanced breast cancer as well. And we plan to explore ovarian function suppression and its management and application in these three cases.

Imm going to start off with just the question of “why ovarian function suppression?” Obviously, we have been focusing on targeting the estrogen receptor for patients who have a diagnosis of ER-positive breast cancer for many years. And, of course, we know the data, and the data demonstrate extremely large benefits in terms of disease-free survival and overall survival for targeting the estrogen receptor in both premenopausal and postmenopausal breast cancer. But obviously more recently, there’s been a real focus on premenopausal breast cancer for a number of very important reasons.

Obviously, for this group of patients, the incidence of breast cancer still is rising, but also again, we know that ER-positive breast cancer makes up the majority of breast cancers that are diagnosed in these younger patients. And utilizing medications that target the estrogen receptor are not only critically important but also important for us to study.

And thinking a little bit about that, we have been, as a field, focusing on the best ways to manage patients who are premenopausal. And, of course, the tools that we have in our toolbox for targeting the estrogen receptor include not only a drug like tamoxifen, but also strategies to target the largest, if you will, pool of estrogen in premenopausal patients. And that’s the ovaries and utilizing LHRH agonists. And then more recently, the use of aromatase inhibitors, which have clearly demonstrated benefit along with ovarian function suppression.

With that in mind, we’re going to get right into this, and we’re going to talk through a number of cases. And the first case that I have here, and I’m going to start out with you Katie, this is a 40-year-old premenopausal woman who had a mammographically detected lesion, biopsy-proven, grade 2 invasive ductal carcinoma, ER and PR was strongly positive, HER2-negative. Her local institution did obtain Ki67. That's not always obtained, but they did, and it was 10%, and she underwent a lumpectomy. Pathology demonstrated a 1.2-cm tumor, grade 1. Sentinel lymph nodes, two of them, were removed and both were negative and then she had an Oncotype Recurrence Score that demonstrated a score of 11. So, this is certainly a case that we commonly see.

And first question of course that comes up is, “in addition to adjuvant radiation therapy, what systemic therapy would you recommend for this particular patient?”

Dr. Katie Ruddy:

Thanks, Matt. So gladly, this patient’s cancer was found very small and lymph node–negative. And with this low Oncotype DX score, I would feel very comfortable advising against chemotherapy. And I don’t even think that this is a case where I would be encouraging ovarian function suppression. Certainly, as you mentioned, we do sometimes now offer ovarian function suppression to premenopausal patients, but this cancer has a very low risk of recurrence with tamoxifen alone. So here I’d probably be suggesting 5 years of tamoxifen as my systemic therapy. That’s not to say that I wouldn't mention ovarian function suppression in the SOFT trial data, but this isn’t a situation where I’d be strongly encouraging that.

Dr. Matthew Goetz:

Great. Thank you very much. Ann, thinking a little bit about the data that really support the use of endocrine therapy, ovarian function suppression, obviously we have data from SOFT and TEXT. But I’m wondering if you could just comment a little bit about the SOFT trial. There was a group of patients there that received chemotherapy, and some patients did not receive chemotherapy. This was based on decisions of their local oncologist. But maybe you could just comment on the SOFT data that would support the decision perhaps to potentially forgo ovarian function suppression.

Dr. Ann Partridge:

I think that’s a really great question. And as you’ll recall, the incremental benefits varied pretty substantially in terms of the absolute benefit in SOFT from the addition of ovarian suppression to tamoxifen, which was the primary analysis. And in fact, there’s a nice risk calculator that I’m sure you're familiar with that Meredith Regan and the team who ran SOFT have actually put out there for people to use in practice that can help you. And they published on it of course as well; it can help one to put the factors in and think about the incremental absolute benefit of treatment. But overall there were two big groups in SOFT. One was the people who got chemotherapy and/or had higher risk markers that their doctors wanted to choose chemotherapy. And that included things like being young or having larger tumors. And then there was a group with more modest risk and that was the bulk of the patients where we still wanted to address the question, “does ovarian function suppression add [a benefit] and if so, is it better with an aromatase inhibitor?” Obviously that’s where it overlapped with TEXT. So for many of us when we, based on those data, now that we have them and we now have pretty good near more than a decade out follow-up. You can see that the incremental benefits for someone who has a small, node-negative, no high-risk features including being very young, which contributed to the higher-risk groups, they don’t seem to get very much benefit from the addition of ovarian suppression in the setting of tamoxifen.

Dr. Matthew Goetz:

I think this is such an important factor because I do think that there is sort of what I would call the “knee-jerk reaction.” I think all of us maybe are susceptible a little bit to this, which is the push to escalate our therapies. And obviously, SOFT and TEXT really demonstrated that there is a time to escalate therapy and thankfully we can improve the outcomes on our patients. But I think as you said, this is a great example of a scenario where perhaps we don’t need to escalate.

Dr. Ann Partridge:

Can I just add something?

Dr. Matthew Goetz:

Yes.

Dr. Ann Partridge:

I think the other place this comes up a lot, Matt, is if someone who’s not tolerating [therapy]. So even if they are high enough risk that you offer the ovarian suppression, let’s say this woman had a lymph node involved. You’d probably offer her the ovarian suppression, but if she weren’t tolerating it and was really miserable, what’s the incremental benefit there? And when you looked all across SOFT, the incremental benefit at 10 years for all-comers was about 1% in terms of survival. And it’s not huge. It’s big for some patients, but across the trial, it’s not huge.

And at a minimum, you kind of want to make sure they’re at least taking the tamoxifen if they’re premenopausal. And I think sometimes people feel like it’s all-or-nothing, and they’ve failed if they don’t tolerate ovarian suppression, which fortunately most people do. But I found in my practice, kind of dialing it down especially for the intolerant is way better than doing nothing.

Dr. Matthew Goetz:

Yeah, this is such a critical point. One of my mentors once said that the drug tamoxifen has probably saved more women’s lives than any other drug in the history of cancer. And I think we sort of forget that as we think about the escalation, and so better that a patient does get that known benefit, then necessarily they get all-or-nothing.

Let’s move on because I think the next part of this case is actually really important and something, Ann, that really is quite germane to the paper that you just presented with regard to the POSITIVE clinical trial. And I’m going to start first with Katie on this and then we’ll move back to you Ann. This particular patient after 2 years of adjuvant tamoxifen desires to attempt pregnancy.

And now she's obviously a little bit older. So at this point, this particular patient would be 42, but certainly clearly not out of the realm of being an unreasonable thing to do. And so we up until recently didn’t have a lot of data about this, but obviously we have some recent data. So I think one of the first questions that patients ask us: “Well gee, if I want to become pregnant, I want to stop the tamoxifen. What is going to be my risk for recurrence?”

Katie, what are your thoughts on this, and what would you counsel this patient? First of all, is that risk going to be higher if she attempts pregnancy and she’s successful, gives birth. But the second thing, of course, is this even possible? Is it feasible?

Dr. Katie Ruddy:

Thanks, Matt, for that really important question. And it’s really been exciting to have results from Ann’s POSITIVE trial that just were presented and published in The New England Journal of Medicine very recently, that helps us with counseling our patients on this. As you know in the POSITIVE trial, Ann and colleagues, and I was happy to work with her on this, enrolled and then followed patients who were interested in becoming pregnant after they had been receiving between 18 and 30 months of adjuvant endocrine therapy for ER-positive breast cancer. So, of course, patients were not randomized to pregnancy or not, this was following patients who wanted pregnancy. They were then encouraged on study to take up to 2 years off of endocrine therapy to try to become pregnant and to carry the pregnancy and then to resume endocrine therapy. The investigators followed both the babies’ outcomes and the women’s outcomes and found very encouragingly that there did not seem to be any increased risk of recurrence beyond what we would’ve seen in a similar group of women who didn’t become pregnant.

And the rate of recurrence seen on the POSITIVE trial was [about] 8% over 3 years. Now that’s not to say that that 8% would actually apply to the woman we just talked about because her risk is going to be lower than average. So, I think her risk is going to be significantly lower than that.

But what’s encouraging here is that we don’t think that taking a break in endocrine therapy to become pregnant will adversely impact that risk. And we also know that there is a very reasonable chance that she could become pregnant. Now, as you allude to age 42 for pregnancy, her natural fertility is not going to be as substantial as it would be at age 32. But women on the POSITIVE trial were allowed to use reproductive endocrinology services to become pregnant. And there was actually a significantly greater than 70% rate of pregnancy and a greater than 60% rate of live birth among those participating. So, I’ll let Ann say more about her trial, but I’m just really enjoying having these data to discuss with my patients.

Dr. Matthew Goetz:

Ann, I’m going to now circle to you. First of all, Ann, congratulations on not only an incredible study, incredible result, but also something that is clearly practice-changing for our patients. One of the questions that comes up commonly, of course, is “what are some of the factors that may or may not influence the success rate of becoming pregnant?” And this particular patient had no prior chemotherapy. Did you see any association between pregnancy and the prior chemotherapy in your study?

Dr. Ann Partridge:

That is a great question, and it is the subject of an abstract that’s going into San Antonio for this coming December, so I don’t want to give away all the punchline. But, of course, women who get chemotherapy are at increased risk of chemotherapy-related gonadotoxicity or ovarian dysfunction. And as you heard from Katie, people on POSITIVE were allowed to use and encouraged, especially if they weren’t getting pregnant early on because we didn’t want them to stay off their endocrine therapy for too long. They were allowed or supported to use reproductive endocrinology services. And indeed, over 40% of women did at some point on the trial use some form of assisted reproduction technology. And so more to come on that. But for what it's worth, I think we’ve been telling patients to preserve their fertility in different ways and discussing it with them, worrying that they might become infertile either from treatment or the time it takes to get through treatment, particularly endocrine therapy. And I think that's been good advice for those who want to have another baby or a baby.

Dr. Matthew Goetz:

Great, thank you very much. And obviously, we look forward to seeing those data at San Antonio.