Metastatic Breast Cancers on the Rise, U.S. Study Shows

Despite improvements in survival, the incidence of stage IV breast cancer increased significantly from 2010 through 2021, according to a U.S. population-based cohort study.

The age-adjusted incidence rate of de novo stage IV breast cancer significantly increased from 9.5 cases per 100,000 females in 2010 to 11.2 cases in 2021, an annual percentage change (APC) of 1.2% (95% CI 0.8-1.6), reported José P. Leone, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues.

Among males, there was also a statistically significant increase in stage IV incidence, from 0.12 cases per 100,000 in 2010 to 0.20 cases in 2021, an APC of 3.7% (95% CI 1.0-6.5), they noted in JAMA Network Open.

Moreover, the incidence of stage IV breast cancer increased significantly across age groups and numerically across all races and ethnicities.

Notably, overall survival (OS) among patients with stage IV disease improved in each successive year, Leone and team reported.

“Prior analyses reported stable stage IV incidence before 2010 despite screening expansion,” they wrote. “In contrast, our findings demonstrate a significant increase beginning in 2010, including among screening-eligible age groups. The underlying drivers remain uncertain and may reflect population-level changes in risk factors, screening patterns, or access to care.”

“These findings suggest that efforts are needed to determine factors contributing to these increases and to identify breast cancer before patients present with de novo stage IV disease,” they added.

In a commentary accompanying the study, Laura C. Pinheiro, PhD, MPH, of Weill Cornell Medicine in New York City, noted that while she agreed with the authors on the importance of identifying risk factors for the increasing incidence of stage IV disease, she also emphasized the need to “better support the multifaceted, complex needs of this growing patient population.”

“Given the tremendous physical, psychosocial, and financial burden experienced by these patients, we should prioritize supporting adults with advanced cancer throughout the cancer care continuum,” she wrote.

For this study, Leone and colleagues used data from the Surveillance, Epidemiology, and End Results (SEER) program to identify 761,471 patients diagnosed with de novo invasive breast cancer from January 2010 through December 2021. Median age at diagnosis was 60 years among all patients, and 63 years among those with stage IV disease; 99.2% were female, and 5.8% had stage IV disease.

The age-adjusted incidence of stages I to III disease also increased in females over the study time period, from 163.0 to 177.4 cases per 100,000 females, but the APC of 0.3% was not statistically significant (95% CI -0.3 to 0.9).

An analysis of stage IV incidence by tumor subtype showed statistically significant increases for triple-negative breast cancer (APC 2.7%, 95% CI 1.4-4.0), hormone receptor (HR)-positive/HER2-negative breast cancer (APC 2.0%, 95% CI 1.5-2.6), and HR-positive/HER2-positive disease (APC 1.6%, 95% CI 0.2-2.9). For HR-negative/HER2-positive disease, the APC was 1.3% (95% CI -0.1 to 2.7), a nonsignificant increase.

Patients younger than 40 years had the highest increase in overall incidence (APC 3.1%, 95% CI 2.2-4.0), which was driven by HR-positive cancers, while those older than 74 years had the highest increase in triple-negative cancers (APC 4.3%, 95% CI 1.9-6.8).

The age-adjusted incidence of stage IV breast cancer increased numerically across all racial and ethnic groups, and was highest overall among Asian and Pacific Islander patients (APC 3.4%, 95% CI 2.4-4.4).

OS improved significantly over time for each successive year among patients with HR-positive/HER2-negative disease (adjusted HR 0.99, 95% CI 0.98-0.99), HR-positive/HER2-positive disease (aHR 0.97, 95% CI 0.95-0.99), and HR-negative/HER2-positive disease (aHR 0.97, 95% CI 0.94-0.99).

The improvement in OS over time in triple-negative breast cancer was not statistically significant (aHR 0.99, 95% CI 0.97-1.01).

Leone and team said the improvement in OS across most subtypes likely reflected advances in systemic therapy, while the lack of a statistically significant improvement for triple-negative disease underscores “ongoing therapeutic challenges in this subgroup.”

They acknowledged that their study had several limitations, including the fact that SEER does not have information on breast cancer screening use or adherence, or about epidemiological risk factors for breast cancer, such as obesity, breastfeeding, and hormone use.

“The absence of these variables limits our ability to assess how differences in screening practices, comorbidity burden, and individual-level socioeconomic or lifestyle factors may have contributed to observed incidence and stage-at-diagnosis trends,” they wrote.