‘Multiplicity of agents’ saturate treatment landscape for de novo metastatic breast cancer
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Key takeaways:
- Most activity in de novo metastatic breast cancer is happening in the medical oncology space.
- Researchers continue to work toward improving survival outcomes, while reducing treatment-associated toxicities.
Significant advancements have been made in the de novo metastatic breast cancer space, including novel agents targeting the HER2 protein and others that enhance anti-estrogen therapies.
“There’s a multiplicity of targeted agents that are approved for de novo metastatic breast cancer that have been shown in clinical trials to produce improved results,” Seema A. Khan, MD, Bluhm Family Professor of Cancer Research, and professor of breast surgery at Northwestern Medicine Feinberg School of Medicine, told Healio. “There is a lot of ongoing investigation with stereotactic body radiotherapy [SBRT] for the treatment of oligometastatic breast cancer, which is not entirely new, but the accumulation of clinical evidence for or against SBRT is relatively recent and ongoing.”
In 2021, results of the phase 1 NRG-BR001 trial showed that treatment with SBRT resulted in no protocol-defined dose-limiting toxicities among patients with oligometastatic breast, prostate or non-small cell lung cancers.
Median survival had not been reached at the time of study publication, with an estimated 2-year OS rate of 57% (95% CI, 38-72), according to Chmura and colleagues.
“In the NRG-BR001 trial, the surprising thing that really points to the importance of systemic therapy is that the two arms with or without SBRT did just as well — they experienced excellent PFS that was very similar and much better than expected by the investigators,” Khan said. “What the researchers had postulated in the beginning when planning the trial was that the SBRT arm would have better PFS in the range of 18 to 19 months, and the systemic therapy without SBRT would have shorter survival. The surprising thing was that the SBRT arm did as expected, but the control arm of systemic therapy did much better than expected, which reflects the efficacy of these newer treatment strategies with medical treatment.”
Other treatment activity
Most of the activity in metastatic breast cancer de novo or otherwise is happening in the medical oncology space, according to Khan.
“One of the things that we have learned over the years is that there is a survival advantage for women who have de novo metastatic disease, which is probably related to the fact that it’s often detected along with the primary tumor and is more likely to have limited metastatic burden,” she said. “In addition, the tumors in those women have never been exposed to medical therapy.”
Experts have also come to learn that de novo metastatic breast cancer is associated with better survival outcomes compared with women who have metachronous metastases.
“These tumors are more sensitive to treatment and often ha a lower metastatic burden,” Khan said. “Still, one cannot tell a patient with metastatic disease, de novo or otherwise, that their tumor will be cured. But with these improving medical treatments, survival certainly has been prolonged during the past couple of decades. There is a clear trend toward improving survival for de novo metastatic disease as well as for metachronous metastatic disease.”
In recent years, PET scans are increasingly being used to identify metastatic lesions.
“Patients who were staged conventionally in the past are still being staged conventionally because that is recommended in the National Comprehensive Cancer Network guideline to stage patients with conventional CT imaging, bone scan, etc., but if these women undergo PET scan instead, they may be found to have one or more minimal metastatic lesions,” Khan said. “In the past, those women were classified as having stage III disease and now they’re being told that they have stage IV disease. There is definitely a stage shift here and that line of division between stage III and stage IV is now blurred.”
Moreover, it is possible that de novo oligometastatic breast cancer may behave like stage III disease, she continued.
“Each patient’s experience depends on the burden of metastatic disease and whether it’s symptomatic,” Khan said. “The other thing with oligometastatic disease is that it is usually not symptomatic but is often found at the time of initial diagnosis. For those women, treatment decisions are more complex from the perspective of how much to treat the oligometastatic disease with local therapy.”
BR002 trial
Researchers conducted the phase 2/phase 3 NRG-BR002 trial to further assess the SBRT doses evaluated in the BR001 trial.
Results of the BR002 trial showed that the addition of SBRT to standard-of-care first-line treatment did not improve PFS among patients with de novo oligometastatic breast cancer.
The findings, presented during the 2022 ASCO Annual Meeting, specifically showed a median PFS of 23 months with standard-of-care treatment vs. 19.5 months with the addition of SBRT.
“BR002 is all retrospective data — there is no prospective unbiased evidence that surgery alone for oligometastatic disease improves survival,” Khan said. “The treatment decisions are a bit more complex, because there’s a lot of patient and physician interpretation of the value of treatment that goes into those decisions. If we have clear-cut results from a clinical trial, it is a lot easier to recommend a specific strategy, but if there no clear-cut results, then there’s a lot of ‘feeling your way through’ the process and a lot of shared decision-making, explaining the pros and cons and the toxicity of treatments that should be considered. Obviously, medical treatment is necessary, but for local treatment, surgery and radiation, the decisions are more difficult because of the lack of good prospective data.”
Ongoing research
Research efforts are ongoing that aim to confirm or refute the results of the BR002 trial, Khan told Healio.
“The results are pretty clear-cut with that trial, but the trial results haven’t been fully published — yet,” she said. “In speaking with Dr. Chmura recently, he explained that the results are not yet published because they are waiting for 5-year outcomes — they want to be absolutely clear on the results of that trial. We should start seeing those results come out in a couple of years.”
Other research efforts are ongoing here in the U.S. and in Korea, where investigators are examining local treatment approaches for de novo oligometastatic disease.
“The results of those trials will be interesting to see,” Khan said. “There are other similar trials conducted in India, North America and Japan that all showed no significant differences in survival between treatment arms but data did indicate a difference in local control — women with de novo breast cancer were less likely to progress if they received local regional treatment for their primary tumor.”
However, the value of local therapy for the primary tumor is not proven at the moment.
“That is another fraught decision for patients with this diagnosis because it seems counterintuitive that it wouldn’t help to remove the tumor in the breast but the argument for locoregional treatments for the primary tumor site is not strong at the moment,” Khan said. “Personally, in my practice, I reserve locoregional treatment for women who have well-controlled distant disease, but their tumor starts to progress locally.
“In that setting, it’s reasonable to offer locoregional treatment for the primary tumor site. But many breast tumors, if they respond at distant sites, will also respond at the local site,” she . “The tumor that may have been 5 cm when the patient was first diagnosed will shrink down to the point that it’s not palpable. We see it with neoadjuvant therapy all the time. Systemic therapy also controls the primary tumor site, and there is only a small minority of women who require palliative treatment for the primary tumor in the setting of metastatic disease.”
Anticipated developments
Experts continue to work diligently toward improving survival outcomes for patients with de novo metastatic breast cancer, while reducing treatment-associated toxicities.
“Medical treatments also carry many toxicities,” Khan said. “What is promising about medical treatment is that many of the newer interventions are not as toxic. For example, with antibodydrug conjugates, such as TDM-1 and trastuzumab deruxtecan [Enhertu; AstraZeneca, Daiichi Sankyo] in patients with HER2-positive disease, they are actually reasonably well-tolerated. Treatment advancements that provide better efficacy with less toxicity are obviously very valuable.”
Another toxicity that has entered the arena with these newer treatments is financial toxicity, according to Khan.
“These treatments are extremely expensive, they are not available across many parts of the world and they are not affordable across many parts of the world,” Khan said. “Ideally, for patients with breast cancer, I would love to see progress toward treatment that is both more effective and less toxic as well as more affordable. All of this is part of the sum total of the patient experience. There are clearly improvements that need to be made in this area.”
Overall, locoregional treatment for patients with de novo disease will entail close attention to prove that it provides an advantage as well as minimizes the known associated toxicities, she continued.
“We should not leave our patients with de novo metastatic breast cancer with toxicities that burden their lives for the remaining time they have,” Khan said.
References:
- Chmura SJ, et al. JAMA Oncol. 2021;doi:10.1001/jamaoncol.2021.0687.
- Chmura SJ, et al. Abstract #1007. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
For more information:
Seema A. Khan, MD, can be reached at s-khan2@northwestern.edu.
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