In this edition of “Applying research to practice,” I highlight a study revealing real-world information about the clinical care of breast cancer patients with deleterious germline mutations.
Dr. Alan P. Lyss
While germline testing among breast cancer patients is becoming more commonplace, it isn’t clear how test results influence patient care. To gain some insight, Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues analyzed data on 20,568 women with stage 0-III breast cancer from the Surveillance, Epidemiology, and End Results (SEER) registries of Georgia and California (JAMA Oncol. 2020 Feb 6. doi: 10.1001/jamaoncol.2019.6400).
The researchers aimed to determine whether women with mutations in breast cancer–associated genes (BRCA1/2 or others) received guideline-concordant care to the same degree as women who lacked deleterious mutations. The authors evaluated guideline concordance with respect to three treatment modalities: surgery (bilateral vs. unilateral mastectomy in women who were eligible for unilateral surgery), radiotherapy after lumpectomy (for women aged less than 70 years with hormonally responsive, ErbB2-negative, stage I cancers), and chemotherapy (among women eligible for consideration of chemotherapy omission)
In alignment with guidelines, many clinicians correctly used genetic test results to guide surgical decisions. For example, 61.7% of women with BRCA mutations underwent bilateral mastectomy, compared with 24.3% who were mutation negative (odds ratio, 5.52). For other pathogenic variants (ATM, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, and TP53), the rate of bilateral mastectomy was still elevated, albeit to a lesser degree (OR, 2.41).
In discord with guidelines, women with BRCA mutations were 78% less likely to receive radiotherapy after lumpectomy (OR, 0.22) and 76% more likely to receive chemotherapy for early-stage, hormone-positive disease (OR, 1.76), suggesting possible trends in under- and overtreatment, respectively. Chemotherapy utilization rates among mutation carriers and noncarriers became more similar after adjustment for clinical and demographic factors.
There are limits on the granularity of the SEER database, such that, if a patient had a mastectomy a year or more after lumpectomy in an effort to avoid radiotherapy, the database would not have reflected that. Clinical factors could have appropriately influenced chemotherapy receipt among patients with mutations, but those additional factors (including patient preference) would not be included in the SEER data.
The authors concluded that research should be conducted to confirm the results of this retrospective, population-based cohort analysis, in an effort to understand the decision-making process and consequences for long-term outcome.
How these findings should influence practice
With every new development, there are challenges – some expected, some unanticipated.
It is now feasible to obtain multigene panel testing reasonably inexpensively. There are concerns about undertesting of patients on the basis of family history alone. And some major professional organizations have endorsed routine gene panel testing for all breast cancer patients.
As a consequence of these factors, genetic test results are routinely available to clinicians who may lack formal training in clinical genetics. Whether these results influence the receipt of evidence-based clinical care is uncertain.
The information published by Dr. Kurian and colleagues is inherently limited by the methodology of a SEER database review. Among other limitations, as the authors comment:
- The genetic test results could have arrived after treatment decisions were made.
- Treatment delivered more than a year after diagnosis would not have been captured.
- There was selection of patients for genetic testing.
- There were few patients with particular germline mutations other than BRCA1/2 on whom to judge whether treatment was guideline concordant.
- The rationale for the treatment choices made by physicians and patients was not available.
- Impact of treatment choices on survival for carriers of deleterious mutations is uncertain.
Nonetheless, these data suggest a need to redouble efforts to educate patients, their family members, and health care professionals about evidence-based guidelines for care and the rationale for those recommendations.
Careful, prospective monitoring of any resultant differences in treatment outcome in patients treated with guideline-concordant and nonconcordant care is needed. When treatment choices appear to systematically deviate from published guidelines with no obvious rationale, it is a wake-up call for all of us.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations.