E29: Refractory and Recurrent Idiopathic Granulomatous Mastitis Treatment: Adaptive, Randomized Clinical Trial

And it can present with a variety of symptoms, most importantly, like, large breast mass that is erythemal, or even fistula, generally it is not, very common disease all around the world, but it can be way more common among certain patient populations. So some surgeons may have a patient with IGM on a daily basis in their clinics, and some may see it once a year.

With that being said, it's been shown that, it is a common disease among Middle Eastern population, including Iranians of course, and Hispanic population as well, especially in your young, reproductive years. And, this demographic also adds another layer of complexity, since many of these patients, might be concerned about the possibility of cancer or, different breast diseases. So there are some challenges that can be associated with IGM, including treatment resistance.

Actually the absence of a proven etiology for IGM, makes it particularly difficult to achieve a complete cure without the risk of remission. And the other challenge is also the recurrence. And even after successful treatment, IGM has a tendency to recur. And this lack of reliable response has complicated patient care, with no general agreement on a standardized approach to treatment. And as of now, no specific clinical guidelines exist.

Which is leaving patients and clinicians facing a landscape of trial and error. Yeah, I, I can I, I, I feel it as you're describing it because I do I have seen these patients in my clinic and, a lot of times it takes, quite a bit of time even before they get the diagnosis. Because, you know, maybe they have been thought to have sort of breast abscess or infectious etiology without recognizing the underlying inflammatory disease component.

Sometimes they go through big surgeries because people are trying to debride the area. But as you know, when it's this inflammatory disease, the surgery is typically not a curative treatment, because the underlying process, autoimmune process, which we maybe don't understand very well, is still in existence. And and so I can, you know, just remember patients as you're talking who have had this persistent or recurrent disease.

Yeah. And exactly as you mentioned, there are like large, treatment approaches that is currently being used, starting from in the observation, some surgeons like, prefer to only observe and do some, you know, antibiotics and low level of, treatment, and some others even do surgery. So, these treatments often yield inconsistent results with some patients responding well, some others do not, as you mentioned. And also each option carries its own set of risks and potential side effects as well.

And again we are dealing with a young patient population generally, which makes it like even more challenging. So in this study, that's why we wanted to address these, pressing needs, focusing on that, this a specific patient population who were resistant and, or show some sort of recurrence the after, their, like, first line of treatment.

And we were generally in this patient population, we were dealing with patients having, more severe form of IGM and, some sort of failure to response to therapy. Okay. And you used, a database or a research collaborative to identify patients. Can you tell us a little bit about how you identified them and how you defined the the disease? Yes. So, the the, this study was done on a, breast, research center in Tehran, Iran, from 2017 to 2020.

And it was done, as a like prospective adaptive clinical trial. So the center was kind of, only breast diseases and a lot of the patients were referred from, other surgeons due to like, you know, due to resistance to therapy. So, that's how we recruited patients, from 2017 to 2020. In the, Breast Cancer Research Center. Okay. And it sounds like, this also was a group of clinicians who were motivated, as you are, to figure out how to address this disease.

And so then you had, specific criteria for defining, the IGM, and making sure that you're looking at, as homogenous a population as possible or, you know, the disease pattern. Yeah. So all the patients. So how would you find a patient was, first of all, the patient undergoing, histopathological confirmation. So they had a biopsy and, in our center. So, the breast pathologist, sees the slides and confirm, the diagnoses of IGM, histopathologically.

And then, how we define recurrence or resistance was, no response to therapy after eight weeks of treatment as, okay, resistance and recurrence of the disease was defined as, reappearance of the signs and symptoms within eight weeks, of the completion, of the therapy And they usually like the first line, that, most of them were getting was, and say antibiotics, drainage and, some dressings.

So they were like most mostly, some sort of supportive care as the first line and, all the patient population were kind of either resistant or recurrent through these, therapeutic approaches. Okay. Yeah. And again, I think, at any age, but, seeing patients who have persistent wounds and pain, I, you know, not everybody has pain as their first presenting symptom.

But again, I've certainly seen a significant amount of pain and and again, the, the challenge and the, life-limiting need to have dressings and, you know, add that into your daily routine is very challenging. Yeah. Exactly. And so most of the patients were actually, really annoyed with their signs and symptoms. Yeah. Being unresponsive. And I think the other thing that you highlight in the paper is the importance of ruling out other causes.

So when we define someone as having IGM, making sure that they don't have tuberculosis or non-tuberculosis mycobacterial infection, it can be associated also with other autoimmune diseases to have inflammation in the breast. So uncontrolled diabetes sometimes is a precipitor of inflammation in the breast as well. So I know you spent some, some time looking at that. And then you also looked at the inflammatory markers in these patients.

Yes. So, all the patients underwent tuberculosis PCR to make sure that they don't have TB and they don't have any, you know, contraindication for getting corticosteroid as well, because that was one of the main, main stem of the clinical trial. And, all the like, clinical and demographic characteristics of the patient, including, blood test or, angiotensin converting enzyme, and antinuclear, antibodies were also assessed, in their blood, in their blood test.

Okay. And so then you defined this group of patients and tell me about the, escalating therapy or the the adaptive responsive therapy methodology, how you kind of picked which therapy to use and how the patients were monitored. Okay. So, everything that's been said, there there were no, like, specific therapy that well, we kind of know that it's going to work for these patient populations.

So for the interest of patient and controlling their symptoms as well as possible, we decided to conduct this study in an adaptive manner, which, we like the the whole clinical trial on three phases. And, we started with three arms. First arm was including, supportive care because, all the patients were referrals. And we also wanted to have that arm to compare with the others, the rest of the arms, the second arm was, high-dose prednisolone, 50 milligram/m² per day.

And the last arm was the lower dose of corticosteroid or prednisolone, which was 12.5mg/m² per day, in addition to methotrexate. So we randomized in the first phase, we included like ten patients in each study arm. And the first point of evaluation was after 1 to 2 months, because it was a like, it was patient dependent. Basically some of them were okay now, like not going back. But the general endpoint was after a month and for the first phase.

And after that, after the first point of evaluation, we saw that almost none of the patients in, arm of supportive care getting drainage was not responding. So we decided to terminate that arm and recruited more patients in, in the other two arms, meaning we continued with, high dose prednisolone. And the other arm was methotrexate plus prednisolone. So we accept more patient.

And the second point of evaluation, was after six month and after six months, we generally, the goal was after seeing remission of the signs and symptoms clinically, we started tapering the drugs, in each patient population. Interestingly, most of the patients in high-dose prednisolone group was kind of, responding to the therapy well. But once we started tapering the drug, we saw, the remission of the symptoms.

Okay. After six months. Yeah. So that's why, again, that was kind of failure to therapy. And in the second phase will be terminated group B, which was high prednisolone. And we only continued with methotrexate in addition to lower dosage, of prednisolone. So you took those patients who had relapse of symptoms after tapering their high dose prednisolone and moved them over to do the lower dose with the methotrexate. Exactly.

So, we continue with 12.5mg of prednisolone in addition to methotrexate again until complete remission, achieved. And then we start tapering the drug. So generally, on average, the whole time of the treatment in group B, which was high-dose prednisolone, was about six months. And in the last group, which were also taking methotrexate was about 18 months. So they continue getting methotrexate for over a year, on a weekly basis.

But, the good thing about the last group was they were able to taper out the, prednisolone very soon. And so the prednisolone was not not needed for symptom control as long as the methotrexate was. Exactly. And the reason that we do not have, the like, methotrexate alone and we added prednisolone to that group is it generally took time for methotrexate to take action. And these patients were really like in pain. And we wanted to take advantage of quick symptom relief of prednisolone.

But generally, after quick symptom relief. And if you're able to taper out prednisolone and continue with methotrexate only. And so then you followed these patients out 3 to 5 years from their treatment. How did they do? Did they have to go back on treatment again? Or how often did they have recurrence of symptoms. Yes. So, for the remaining arm, which was methotrexate, and for these alone, we saw about 94 to 97%, complete cure. So we, we just we didn't.

Yeah. We didn't, have patients coming back to the clinics with their recurrence. When they’re getting, like, complete, methotrexate course. And. Yeah, that was the, like the best treatment arm that we had in this study. So that the other arms, as you said, the observation and supportive care really didn't lead to disease control. Right. And then in the patients with the high-dose prednisolone, did you have some of those patients achieve control?

Yeah, we had about, 14 to 15% of the patients respond to the therapy. And in this patient population, I would say 14 to 15% had this as their sign and symptom, cured without recurrence because, that's the kind of treatment failure that we saw in this patient population was mainly a recurrence. So we had about, 15 patients, 15% of the patients without recurrence of their signs and symptoms.

And then how did the patients in these two treatment arms do in terms of side effects of medications or other, symptoms that they experienced during treatment? Yeah. Actually there were not... no significant differences in terms of the side effects among the groups getting, methotrexate, methotrexate, on the prednisolone. So generally supportive care, they, they didn't have that much of side effects because like, they were getting, regular, maybe antibiotics.

Yeah. Yeah. And also, it didn't, like, take longer than 1 to 2 months, so they're not under like long, of course, of treatment. But, in the other two groups, we obviously saw some patients with high level of, blood glucose, which was still like lower than 120 and we had some weight gain, about three, four kilogram. But, generally we didn't have, much, or severe side effects.

And they were all back to get back to normal after, the, course of that, their treatment, and the most frequent, symptom that we had among methotrexate patients was, some GI symptoms, and some sort of headaches, so that I will say there were nothing, bad that we had to just, you know, discontinue the drugs. Well, I think that's good news, because, again, I worry about patients, particularly being on steroids, corticosteroids for a long period of time, but autoimmune modulating drugs as well.

So it's good to hear that overall, it sounds like it was pretty well tolerated. And then maybe there are a couple of options. I suppose if someone couldn't take methotrexate that you could try the high-dose steroids. It's just, not as good at achieving true remission of the disease. Yeah. What do you think about sort of, the longer term follow up? Do we need longer term follow up to see if these patients recur ten years later? Have you have you seen, you know, that that the disease recurs?

After that in some patients, in other studies or literature reports? Not actually most of the if, any recurrence would happen most of them would be within five years. So in our patient population, I mean, it's obviously not after ten years, but in other studies in our institute, as well as the literature review that were done and also, a great surgeon that I was, I had the pleasure to work with and their experience, it's usually within five years.

So there, there seems to be like, no need for ten years or longer term follow up for these patients. That's great to hear. So, you know, over 90% cure rate, of this disease. It is a significant time to be on treatment 18 months. But to hear that you're able to achieve cure in most of the patients I think is a great outcome.

And particularly knowing that this can be a difficult disease to treat, I don't know that the paper, fully can capture that the experience of the clinician at the bedside who's seeing the patient back and, evaluating whether they need an additional drainage for an abscess or another course of antibiotics and reassuring them, when they're on the medication, that we expect their symptoms to get better.

I mean, there's a lot of helping them through the the stress and anxiety and the symptoms that they're experiencing from the disease that you kind of talked about in the beginning. Yeah, I also like these 18 months is kind of the average. So you can after complete remission you can always start tapering the drugs first of all. And then also I want to again point out that these patients were kind of, you know, more toward more severe side of, the disease and kind of, you know, unresponsive to.

Yeah. So it's possible, I think I hear you saying that in other patients, you might not need to keep them on medication for as long that you intentionally selected, a group of patients with more severe granulomatous mastitis. Exactly, exactly. And it's a good number.

We talk a lot in research studies, right, about the the, numbers and the power of the study, but the 300 patients with severity of that granulomatous mastitis, I think that's a pretty good number for this uncommon disease of the breast. So you were able to collect a good, a good number of patients from the specialized hospital. Yeah, we exactly were kind of a referral center.

So we take advantage. Yeah. And, are there any, caveats about applying these study results to patient populations or things that you do? For instance, do we need to worry about patients being on these medications, if they're pregnant or lactating? Do you have any experience or suggestions for applying their results?

Yeah. So, some other parallel studies that are being done, in our institution, we are trying to find other, ways for those patient that may might have some contraindication for getting methotrexate. Exactly as you mentioned, such as pregnant women or, women in their lactation. So it seems, what we found and, is like another option can be, azathioprine, other, yeah, that azathioprine can be replaced.

So the thing was, patients, are not, tolerating, azathioprine as well as methotrexate, but it can be an alternative, for patients who have contraindication for getting methotrexate. Another option is intralesional, like injection, of the steroid into the lesion. Also another prompt which can help to reduce the dosage.

And the exposure up the whole body and system to corticosteroid therapy, but again the another problem with that again is that complaints of the patient, which can be a bit painful for them for. But these two other alternatives also can be considered for patients. It's good to know that there are additional options.

And again, I've seen, some studies reporting that use of intralesional steroids such as triamcinolone along with the systemic therapies, or for patients who are, having persistent symptoms with systemic therapy. And as you mentioned, the systemic effects of a corticosteroid or azathioprine or methotrexate may be hard for patients to tolerate. So having a number of different options that can help us control this difficult disease makes a lot of sense to me.

Well, I want to thank you for your time today and, to you and all of your research team. I think that what I have experienced and what I've heard from colleagues is that this is often a clinical dilemma. And, and it requires a lot of investment of time to be able to care for patients experiencing granulomatous mastitis or idiopathic granulomatous mastitis, particularly those who are refractory to treatment or have relapsing disease.

So thank you for helping us know how to take care of our patients better. Thank you so much for your interest in the study. Thank you for listening to the Journal of the American College of Surgeons Operative Word podcast. If you enjoyed today's episode, spread the word on social media by using the hashtag #JACSOperativeWord. Subscribe to The Operative Word wherever podcasts are available, or listen on the American College of Surgeons website at facs.org/podcast.