Strategies needed to reduce death due to low-risk breast cancer
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Key takeaways:
- Most breast cancer deaths result from stage I or II disease due to volume of diagnoses and improved treatments for high-risk disease.
- Better monitoring and treatment compliance could reduce mortality.
Most breast cancer-specific deaths occur among patients diagnosed with stage I or II disease rather than more advanced disease, according to a SEER database analysis.
Mortality rates in general are low for people diagnosed with stage I and low-risk stage II breast cancers; however, the higher incidence of earlier-stage cases and improved treatments for high-risk disease have dramatically shifted the burden of breast cancer mortality during the past 2 decades.
“Drug development efforts and all the improvements in breast cancer death are really happening in the high-risk stage II and stage III disease setting,” Lajos Pusztai, MD, DPhil, medical oncologist and co-director of the genomics, genetics and epigenetics program at Yale Cancer Center, told Healio.
“Patients diagnosed with stage I disease had the same chance to die in 2000 as in 2017, which is the last data point in our paper, but I think it holds up even today,” Pusztai added. “There are no new treatment approaches for these patients. If we want to improve breast cancer deaths at the population level, then we need to come up with strategies to reduce death from low-risk breast cancer.”
Increased emphasis on patient compliance with hormone therapy, as well as improved monitoring for recurrence, could be key components of those efforts, Pusztai said.
Background and methods
As Healio previously reported, an American Cancer Society report released earlier this year estimated 313,510 new breast cancer cases would be diagnosed this year, and 42,780 people would die of the disease.
Incidence has increased over time. Mortality has decreased 40% since 2000, though it slowed from a 2% to 3% decline during the 1990s and 2000s to 1% since 2011, according to study background.
“There have been many publications that looked at recurrences for patients with particular stages of breast cancer,” Pusztai said. “We asked a different question: What fraction of patients who die each year from breast cancer presented with stage I, II, III or IV disease when they were first diagnosed?”
Researchers used multiple SEER databases to assess breast cancer incidence and disease-specific mortality between 2000 and 2017.
The analysis included data from 786,537 women (median age, 60 years; 89.63% non-Hispanic/ Latino) diagnosed with breast cancer and 103,855 (median age, 59 years; 90.26% non-Hispanic/Latino) who died.
Contribution of annual breast cancer deaths by each disease stage and trends over the past 2 decades served as the primary endpoint.
Results
Diagnoses of stage I breast cancer increased between 2000 and 2017 (48.8% vs. 53.8%), whereas diagnoses of stage II (35.3% vs. 34.9%) and stage III (13.8% vs. 9.9%) breast cancers declined during that time.
Breast cancer-specific survival remained stagnant for stage I disease between 2000 and 2014 but “increased significantly” for stages II, III and IV, researchers wrote.
The proportion of stage I (16.2% vs. 23.1%) or stage II (30.7% vs. 39.4%) disease that contributed to annual breast cancer-specific mortality rose significantly from 2000 to 2017. The proportion of stage III (36.4% vs. 30.3%) or stage IV (16.6% vs. 7%) disease that contributed to annual breast cancer-specific mortality declined sharply during that time.
However, contribution of disease specific mortality to all-cause mortality among people with stage I or stage II disease decreased during the same time period (71.6% vs. 53.5%), indicating that most of these patients do not die from their breast cancer.
“We were, initially, surprised to see the excellent patient-level survival yet large contribution to overall breast cancer death of patients with stage I and II breast cancer. But thinking about it more carefully, it’s perfectly logical,” Pusztai said. “These patients dominate breast cancer death because of the very large number of cases diagnosed at early stage, and we are getting better and better to avoid recurrences and death in high-risk stage II and III disease, where all new adjuvant therapies are introduced.”
Guidelines may hinder progress
Breast cancer deaths resulting from low-risk disease could be lowered with more aggressive therapy, similar to what is used in higher stage disease, but that could result in excessive toxicity and costs for the vast majority of patients with stage I or stage II disease, Pusztai said.
“It could reduce the 6% to 8% death rate to 4% — or maybe 3% — but it would also imply that 92 to 94 out of 100 patients get overly aggressive therapy with side effects and enormous costs without personal benefit,” he said. “That’s not a way forward.”
Instead, Pusztai emphasized the need for patients to finish their currently standard of care treatment. For patients with ER-positive stage I or stage II breast cancer, this is endocrine therapy for 5 to 10 years.
“The literature suggests that few women complete their 5 or 10 years of hormone therapy,” Pusztai said. “As much as half of patients don’t complete their treatment because of side effects and a perception that their risk is low and, therefore, the benefit is little — perhaps not worth the side effects.
“I think there is room for us in the health care community to help patients comply with their long treatment plans,” he added. “That’s one simple and practical way to move forward.”
Another emerging potentially important strategy to reduce disease-specific mortality is improved monitoring for recurrence, followed by early intervention when relapse is imminent.
Current follow-up guidelines recommend clinic visits every 3 to 6 months for at least 5 years. However, imaging or molecular testing is not recommended unless patients describe symptoms that could be caused by metastatic recurrence, Pusztai said.
These recommendations stemmed from American Board of Internal Medicine Foundation’s Choosing Wisely initiative, which aimed to reduce costs of care by discouraging use of tests or procedures that are unnecessary or potentially cause more harm than good.
“The Choosing Wisely strategy and ASCO breast cancer follow-up guidelines made sense 10 years ago,” Pusztai said. “But I think it needs to be revisited because of the introduction of highly sensitive molecular tests than can detect recurrence before it becomes symptomatic or even detectable by imaging, and the availability of effective new therapies that prolong survival even in large volume metastatic disease.”
Pusztai said he is hopeful that testing circulating tumor DNA (ctDNA) and treating patients at a molecular relapse stage, defined as being ctDNA positive without imaging evidence of cancer recurrence, could avoid a metastatic recurrence and ultimately prevent breast cancer death.
“The clinical validity of several ctDNA assays has been proven. The vast majority of patients who have circulating tumor DNA in the blood will experience a metastatic recurrence in 8-12 months,” he said. “However, [whether] starting a new treatment for molecular relapse could improve survival has not yet been proven. Treating molecular relapse has worked in leukemias, but this strategy is yet to be tested in breast cancer.”
Cost remains a barrier to implementation of these studies but there are several ongoing clinical trials that address this clinical question, Pusztai said.
For more information:
Lajos Pusztai, MD, DPhil, can be reached at lajos.pusztai@yale.edu.
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