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Novel research examines elimination of radiation in certain patients with HER2-positive disease
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Historically, HER2-positive breast cancers have been among the most challenging to treat. These cancers generally grow and spread more quickly than other subtypes of breast cancer. They also correlate with a worse prognosis.
However, recent developments in the therapeutic armamentarium have rendered it a much more manageable disease.1 A novel study by researchers at The University of Kansas Cancer Center aims to determine whether radiation can be eliminated entirely from the treatment protocol for certain patients with early, HER2-positive breast cancer. Melissa Mitchell, MD, PhD, assistant professor of radiation oncology at The University of Kansas School of Medicine, and colleagues are investigating ways to reduce potentially dangerous and toxic components of treatment, including radiation.
"The treatment drugs have just become so effective that it made us think that maybe we could scale back and spare patients the side effects of radiation," Mitchell said in a press release.
Mitchell and colleagues are conducting a study to evaluate responses to treatment with or without radiation among women aged 50 years and older with stage I or II, node-negative, HER2-positive breast cancer. The primary objective of the study “is to describe the rate of local control in patients with HER2-positive early stage breast cancer with a complete response to chemotherapy and lumpectomy alone.”
The researchers will offer recommendations about whether or not to continue trastuzumab (Herceptin, Genentech), with or without pertuzumab (Perjeta, Genentech), for a full year of therapy following surgery as the standard of care.
“All patients are required to undergo neoadjuvant chemotherapy,” Mitchell said. “We are allowing eligible patients to receive some of the newer chemotherapy regimens.”
Following the completion of chemotherapy, participants will be given the choice to enter one of three treatment groups: radiation without lumpectomy; radiation following lumpectomy with a sentinel lymph node biopsy to demonstrate pathologic complete response; and elimination of radiation after lumpectomy with a sentinel lymph node biopsy that confirms pathologic complete response.
“Women who omit radiation after lumpectomy will undergo follow-up examinations every 3 months for 5 years,” Mitchell told Healio in an interview. “We will collect data about local, regional and distant recurrence at each follow-up visit.”
Study protocols require that all patients must have primary tumors smaller than 5 centimeters.
Many of the novel therapies, such as trastuzumab (Herceptin, Genentech), destroy HER2 cells directly without damaging healthy cells nearby, according to Mitchell.
“These drugs have had a dramatic impact on overall survival in the HER2-positive population,” she continued. “We are seeing OS and local control rates in the 95% range with low toxicity. This raises the question of whether we can eliminate surgery or radiation. There will be trials looking at the elimination of both.”
Simon Fung-Kee-Fung, MD, assistant professor of oncology in the Department of Radiation Medicine at Roswell Park Comprehensive Cancer Center, discussed the potential impact of this approach with Healio.
“This study could become the first group to report the rate of locoregional failures within the first 5 years among patients with favorable-prognosis breast cancer in whom omission of radiotherapy has not been studied previously,” he said. “This trial may identify a group of patients for further study.”
Trials like the one being conducted by Mitchell’s group, along with an increasing number of others like it, raise larger questions about the wisdom, safety and utility of reducing or eliminating radiation in women with HER2-positive disease and other malignancies.
Benefits of eliminating radiation
One of the most important advantages of this approach is that omission of radiotherapy may limit or avoid acute toxicity, including fatigue and radiation dermatitis, according to Fung.
Elimination of significant adverse events would be extremely beneficial to patients, Mitchell said.
“Toxicity burden is the key to understanding why radiation should be eliminated,” she said. “In the short-term, there is painful burning at the site of radiation, but this complication can last for years.”
Regarding long-term toxicities associated with breast-only radiotherapy, Fung cited lymphedema, worsened breast cosmesis and cardiac toxicity in women with left-sided cancers.
“Radiation leaves scars and burn marks, along with cosmetic changes in the contour and shape of the breast, that lead to patient dissatisfaction with treatment,” Mitchell added. “If we can offer a treatment that improves these outcomes but does not impact local control and survival, we should be doing that. We need to see, with imaging and biopsy, if we can eliminate surgery and/or radiation, at least in some populations.”
The cosmetic impact and the fatigue have a significant effect on quality of life, according to Mitchell. She suggested that the clinical community must consider these factors that enable patients to get back to work and their lives more quickly.
“Decreased work productivity and quality of life among survivors leads to financial strain for both the patient and the U.S. healthcare system and economy overall,” she said.
For Fung, understanding the clinical implications of eliminating radiation must still be at the forefront of treatment decision-making.
“When considering the reduction or elimination of radiation in populations of women with breast cancer, we have seen slightly worse statistical rates of local control,” he said. “Most recently, at the San Antonio Breast Conference in 2018, the results of NSABP B-39/RTOG 0413 were reported. Like studies seeking to decrease the duration of trastuzumab, this study failed to prove non-inferiority of accelerated partial breast irradiation when compared with whole breast irradiation.”
Fung noted, however, that the absolute differences in ipsilateral breast tumor recurrence and relapse-free interval were small at 10 years of follow-up.4
“This is likely to hold true for omission of radiation in this patient population,” he said. “Adjuvant radiotherapy is likely to provide superior local tumor control. However, if the benefit is small, for a carefully selected patient population, omission may be reasonable to consider if the toxicity of daily radiotherapy treatment is expected to outweigh the benefits.”
Potential drawbacks
Fung also laid out some of the potential concerns with eliminating radiation in this population.
“One issue is that, in patients with small tumors who have had an excellent response to neoadjuvant chemotherapy, it may be difficult to identify the extent of the entire tumor bed at the time of post-chemotherapy, pre-surgical imaging,” he said. “The resection of the entire tumor bed to be submitted for pathologic evaluation would be relevant to ensuring that no residual disease remained. This would be crucial in the consideration of de-escalating local therapy.”
When de-escalating or eliminating any component of cancer therapy, there are always concerns, according to Mitchell.
“We still have to consider whether this will lead to a higher risk of complications downstream,” she said. “This is why all of the patients on our study will be followed for a minimum of 5 years. These tumors are fast-growing, so they will likely grow back within that time; we adopted a built-in protocol to review this.”
Communication with patients in clinical trials is also pivotal, Mitchell continued.
“Patients know they are opting for less treatment than what is available,” she said. “They are willing to help us learn whether we can eliminate certain parts of their treatment without losing effectiveness and without incurring any additional safety concerns.”
Making systemic change
As trials examining reduced or eliminated radiation in HER2-positve breast cancer proliferate, the clinical community will have to decide how to update protocols.
Radiation dose reduction in the form of hypofractionation when targeting the breast without additional fields to target the regional lymph nodes was addressed recently in a clinical practice guideline on whole breast irradiation from the American Society for Radiation Oncology.
“Adoption of radiation dose reduction and omission around the United States has been very slow in the wider community for patients with even better prognoses, such as favorable-risk DCIS or hormone receptor-positive breast cancer,” Fung said, adding that the slow uptake is happening despite a growing body of evidence.
Hypofractionated whole breast irradiation may be offered regardless of HER2 receptor status or the receipt of chemotherapy, trastuzumab or endocrine therapy prior to or during radiation, Fung continued.
“However, in the approach being investigated [by Mitchell and colleagues], omission of radiotherapy is currently investigational-only and should not be offered to patients outside of a clinical study,” he said.
One way to move forward with the elimination of radiation is to think about the specific populations in whom it may be a viable option, according to Mitchell.
“There are a lot of groups looking at eliminating radiation in women over 70 years who have hormone receptor-positive, HER2-positive disease,” she said. “There is short-term follow-up in patients older than 65 years and other studies looking at patients aged 50 years and older.”
Other groups to consider are patients with luminal A breast cancer, which Mitchell described as a “favorable hormone” for eliminating radiation.
“Hopefully, this is another group in which we can look at this as an option,” she said. “Colleagues from across the country are looking at these different populations and asking important questions about the necessity of radiation therapy in breast cancer.” – by Rob Volansky
References:
American Cancer Society. Breast cancer facts and figures 2017-2018. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed March 20, 2019.
KU Medical Center News. KU Cancer Center researcher investigates eliminating radiation for HER2-positive breast cancer. Available at: http://www.kumc.edu/news-listing-page/mitchell-her2.html. Accessed March 20, 2019.
ClinicalTrials.gov. Omission of radiation in patients with HER2-positive breast cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT03460067. Accessed March 20, 2019.
Vicini FA, et al. Abstract GS4-04. Presented at: San Antonio Breast Cancer Symposium; Dec. 4-8, 2018; San Antonio.
Smith BD, et al. Pract Radiat Oncol. 2018;doi:10.1016/j.prro.2018.01.012.
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