Why isn't neoadjuvant endocrine therapy used more in the United States for postmenopausal women with early-stage breast cancer who are interested in breast-conserving surgery?
The ACOSOG Z1031 trial showed that neoadjuvant endocrine therapy for appropriate patients results in a higher rate of breast-conserving surgery than neoadjuvant chemotherapy.[1]
And compared with combination chemotherapy, neoadjuvant endocrine therapy as monotherapy with an aromatase inhibitor (AI) has similar clinical response rates and radiologic response rates, but with lower toxicity.[2]
What will it take for clinicians to consider using it more for appropriate patient populations?
Adjuvant endocrine therapy has historically been used to treat patients with locally advanced breast cancer or those who were elderly or considered too frail for chemotherapy, according to Mathew J. Ellis, MD, a professor and director of the Breast Center at Baylor College of Medicine in Houston, Texas, and a long-time proponent of neoadjuvant endocrine therapy.
Old habits die hard.
"Maybe it's just that old habits die hard," said Dr Ellis. "The question is: How do we get people to change their practice?"
Strong evidence has had little impact. After the ACOSOG Z1041 trial was published in 2011, there was only a small (though statistically significant) increase in the use of neoadjuvant endocrine therapy, from 2.6% before and during Z1031 to 3.2% posttrial, a period from 2004 to 2012.[3]
Responses with neoadjuvant endocrine therapy are slower than what is seen with neoadjuvant chemotherapy, and this can affect the treating physician's comfort level, said Laura M. Spring, MD, a clinical/translational investigator and breast medical oncologist at the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, Massachusetts.
"If you're not sure a therapy is working, you may be hesitant to keep someone on it and not proceed with surgery," Dr Spring said. "That's one reason we need better techniques to monitor whether treatment is working or not."
Another possible reason for the underuse is that lately surgeons are less interested in breast-conserving surgery, Dr Ellis said. He noted that for many cancer patients, the primary physician they see is the surgeon.
"The mastectomy rate has been going up, so there may be a countercurrent of mastectomy reconstruction, which is going against the neoadjuvant endocrine therapy concept," a concept that essentially promotes breast-conserving surgery, he said.
There might also be economic advantages for oncologist to give neoadjuvant chemotherapy as opposed to neoadjuvant endocrine therapy, he said, "but if that were the case, we wouldn't be using Oncotype DX® to guide therapy, because obviously that reduces the amount of chemotherapy administration as well."
We may just be failing to communicate the advances in this approach.
Dr Ellis said that neoadjuvant endocrine therapy is being increasingly used in academic practice, "but 80%-85% of patients are treated in community practice; that's where underutilization is. We may just be failing to communicate the advances in this approach to the general community."
Frankie Ann Holmes, MD, a breast cancer researcher with US Oncology in Houston, Texas, said that she was not aware of any surgeon bias against neoadjuvant endocrine therapy, "although I can imagine there are surgeons who worry that the patient [offered neoadjuvant endocrine therapy] will walk out of their office and go somewhere else."
Dr Holmes said that she believes many surgeons take their cues from the medical oncologist if the medical oncologist has evidence.
"They've now come to understand that with Oncotype not all of their patients necessarily need adjuvant chemotherapy, so why would they all get adjuvant chemotherapy?" she said.
Patient Attitude, Education
Judy C. Boughey, MD, a professor and research chair of the Department of Surgery at Mayo Clinic in Rochester, Minnesota, said that one of the biggest challenges to using both neoadjuvant chemotherapy and endocrine therapy is patient attitude.
"The patient says, 'I have a cancer, cut it out!'" Dr Boughey said. "As a surgeon, I see that front line, and that's where the journey starts, discussing the optimal modalities for best long-term survival."
"For the estrogen receptor (ER)-positive breast cancer patient, we are pretty comfortable saying, 'We can do the surgery, and then you need to take the endocrine "tablet therapy" for 5 years or maybe longer.' It's easy for the patient to accept that," she said. "But compare that with, 'We're going to give you hormone therapy for 4-6 months, and we'll see how your tumor responds and then do surgery.' That's a real frame shift for that patient—that's where a lot of patient education is needed about the potential advantages."
Dr Boughey said that one of the biggest advantages of neoadjuvant endocrine therapy is its ability to shrink the tumor and conserve the breast, as shown in the original ACOSOG Z1031 study.
"A motivated woman who wants to conserve her breast will often consider this approach," Dr Boughey said. "But then there are women who have a larger tumor and want a mastectomy. And there are women with a smaller tumor, and the breast could be preserved, but they say, 'Why take hormone therapy now when I could have surgery now and take the hormone therapy later?'"
"One of the easy ways to talk to a patient about this is to say, 'You're going to be on this drug for 5 years. If we cut the tumor first and then put you on [the drug] for 5 years, we really don't know how well that drug works on that tumor. If we treat you for 6 months first and see how well your tumor responds, then after surgery at 6 months I'm going to be really comfortable with you being on that drug for 4 and a half years more because I'll know that tumor responds well to that drug," Dr Boughey said.
Lack of Clear Guidelines
Dr Spring said that besides a lack of comfort among some physicians and patients, underuse of neoadjuvant endocrine therapy occurs in part because guidelines on its use are not specific.
"There is a lack of clear guidance over what the appropriate patient population is," Dr Spring said. "The National Comprehensive Cancer Network guidelines talk a bit about who should receive endocrine therapy in the preoperative setting, but the current guideline only says it could be offered to those with strongly hormone receptor-positive tumors; it doesn't say much more than that."
The guidelines do say, however, that AIs or tamoxifen could be used and that the preferred endocrine option for a postmenopausal woman is an AI, as several studies have shown AIs to be more effective in the preoperative setting for postmenopausal women, she added.
"Endocrine therapy in the preoperative setting could gain greater use if it [was] further explored in clinical trials in combination with novel therapies such as targeted therapies," Dr Spring said. "The studies combining endocrine therapy with cyclin dependent kinase (CDK) 4/6 inhibitors are very exciting."
She said that primary results from the phase 2 LORELEI study, just presented at the European Society for Medical Oncology meeting in Madrid, showed that adding the phosphoinositide 3-kinase (PI3K) inhibitor taselisib to letrozole before surgery significantly improved outcomes for patients with early breast cancer that was both ER-positive and human epidermal growth factor receptor 2-negative.[4]
Those Most Likely to Benefit
Patients most likely to benefit from neoadjuvant endocrine therapy are postmenopausal, ER-positive, grade 1-2, and with levels of the proliferation marker Ki-67 at less than 30%, Dr Ellis said.
"Chemotherapy is probably not particularly effective for this group in any event," he said.
Patients more likely to be considered for chemotherapy would be those with higher-grade tumors or node positivity on fine-needle aspiration, ultrasound, or MRI. But there is some controversy here, Dr Ellis said, in that chemotherapy has an extremely modest effect on overall survival anyway in postmenopausal women.
Optimal Duration Unknown
The optimal duration of neoadjuvant endocrine therapy is unknown. Most patients are treated for 3-6 months, mainly because that was the duration used in some of the early trials.
"Three to 6 months of endocrine therapy is perhaps not long enough for all patients," Dr Spring said.
Dr Spring cited a study by Giovanni Allevi and colleagues[5] that compared letrozole for 4 months versus 8 months versus 12 and showed a higher clinical response rate with longer use.
And a recent small trial with 33 patients showed a 55% response rate, which was achieved in a median of approximately 10 months.[6]
For her patients, Dr Boughey begins with 4-6 months of therapy because, "from the patient's perspective, 4-6 months they can accept. For a patient who is responding, if I'm seeing tumor shrinkage, I'm very happy to continue for even longer. And if I can give them reassurance that the endocrine therapy is working, either by physical exam or ultrasound measurements, and they're tolerating it well and not having side effects, they're often very willing to continue on it."
The thing about giving hormone therapy is not to give it and forget it.
"The thing about giving hormone therapy is not to give it and forget it," Dr Holmes said. "I follow these patients just like if they're on chemotherapy. I see them every 3 weeks—or, if they're older, I might see them once a month—to make sure they're taking their medicine and that they're continuing to respond."
Dr Boughey, a graduate of the University of Cambridge, said that there is a much higher use of neoadjuvant endocrine therapy in the United Kingdom, due in part to monitoring time to treatment.
"In the United Kingdom, you can get the patient a prescription and get them on endocrine therapy in a week or so of diagnosis, but you can't very often get them to the operating room in a week. The National Health Service (NHS) pushes time to treatment and monitors it. Neoadjuvant endocrine therapy has been one way the NHS is dealing with the volume of women with breast cancer by initiating treatment in a very short time line."
ALTERNATE Study
Treating a patient with drugs while the tumor is in place increases the probability of breast-conserving surgery, but it also allows the oncologist to assess tumor response as a marker of how the treatment is working. There is evidence that the degree of Ki-67 suppression after neoadjuvant endocrine therapy is a reliable short-term surrogate for the adjuvant potential of endocrine drugs, at least in postmenopausal women, Dr Ellis said.[7]
"This suggests that neoadjuvant data could be used to design adjuvant endocrine trials for breast cancer," he said. "One of the things we've inadequately appreciated is how neoadjuvant endocrine therapy really identifies which tumors have intrinsic resistance."
Dr Spring said that the ongoing Alliance ALTERNATE study, led by Cynthia Ma, MD, PhD, an associate professor at Washington University Medical School, is a great example of using specific interventions to understand if endocrine therapy is working.
In the ALTERNATE trial—Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer NeoAdjuvant Treatment—postmenopausal women with ER-positive T2-4 tumors receive neoadjuvant anastrozole, fulvestrant, or both, followed by surgery and adjuvant endocrine therapy for 4.5 years.
Patients undergo an early biopsy to assess Ki-67 status to determine if it is being suppressed. If not, that is perhaps a patient with primary endocrine therapy resistance who would do better with chemotherapy.
"That really helps—from the patient's standpoint, they're not getting chemotherapy automatically when they could get better benefit without chemotherapy, but those who do need chemotherapy will benefit from it," said Dr Boughey, who said that she uses that approach even for patients not on study.
"Once the Alliance ALTERNATE trial is completed, looking at this principle of chemotherapy sparing, the evidence could be even more compelling for use of neoadjuvant endocrine therapy," Dr Spring said. "And it would make clinicians more comfortable using neoadjuvant endocrine therapy if there was a reliable early tool to get a sense if the therapy is useful or not."
Optimal Endocrine Therapy: Single Agent? Combinations?
At the moment, the choice for neoadjuvant endocrine therapy would be any of the three approved AIs, Dr Ellis said. When the results of the ALTERNATE trial are known, which are expected in 2019, that might give an answer of whether fulvestrant is more effective in this setting, "a concept mildly encouraged by comparisons of fulvestrant and anastrozole in the metastatic setting," he said.
One question being addressed in the neoadjuvant setting is whether another drug can be combined with an endocrine drug to improve effectiveness.
There's no drug company behind this.
"It is somewhat disappointing that adding everolimus to endocrine therapy or adding an AKT inhibitor or a PI3K inhibitor doesn't increase the pathologic complete response rate," Dr Ellis said. "And adding a toxic additional drug doesn't seem to be producing more major regressions than the endocrine drug itself, which is also a little disappointing."
Dr Ellis said that CDK4/6 inhibitors are promising because they suppress Ki-67 much more than the AI alone.
"That's obviously a good thing, and we're studying them in the adjuvant setting," he said. "But in the neoadjuvant setting, it's not clear we are getting more dramatic regressions with the CDK4/6 inhibitors than with the endocrine drug alone."
But interestingly, in the CDK4/6 world, there is the possibility of Ki-67 monitoring to help with decisions about who should get a CDK4/6, he said.
"If you give neoadjuvant endocrine therapy, and the Ki-67 is ablated by the endocrine drug alone, the patient is probably not going to benefit from adding the CDK4/6 inhibitor. But if you give the neoadjuvant aromatase inhibitor, and there's still proliferation, and that proliferation can be suppressed by the CDK4/6 inhibitor, that's clearly a benefit," he said.
After discussing the new targeted agents, Dr Ellis noted that in the ongoing neoadjuvant endocrine therapy research, "there's no drug company behind this. This is a practice advance based on diligent academic research."
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου