JAMA Netw Open
Metastatic breast cancer at diagnosis is on the rise
Clinical Takeaway: The growing share of breast cancer diagnosed after it has spread warrants close attention to whether eligible patients are reaching screening and timely diagnostic follow-up, particularly in groups where late-stage presentation is rising fastest.
Breast cancer incidence has been climbing roughly 1% a year, but most analyses haven't separated whether that increase is driven by early or late-stage disease at first diagnosis. This study examined U.S. trends in de novo stage IV breast cancer, or cancer that has already spread to distant organs by the time it's first diagnosed, to clarify what is actually changing.
The picture is one of more patients reaching diagnosis after disease has already spread, despite available screening. Age-adjusted incidence of stage IV disease rose from 9.5 cases per 100,000 women in 2010 to 11.2 per 100,000 in 2021, an annual increase of 1.2%. The share of new breast cancer diagnoses presenting as stage IV also climbed, from 5.6% to 6.0%. A sensitivity analysis restricted to 2010 through 2019 showed a similar trend, suggesting the rise wasn't solely a pandemic effect.
The increase was broad-based rather than concentrated in a single subgroup. Stage IV incidence rose for triple-negative disease (2.7% per year), HR-positive/HER2-negative (2.0%), HR-positive/HER2-positive (1.6%), and HR-negative/HER2-positive (1.3%, not statistically significant). Adults under 40 had the steepest increase (3.1% per year), which was driven by HR-positive cancers.
Although men account for less than 1% of breast cancer, advanced disease in men climbed 3.7% per year, faster than in women. Non-Hispanic Black patients were also more likely than other racial and ethnic groups to present with stage IV disease, consistent with persistent disparities in stage at diagnosis.
Survival in metastatic disease improved modestly across most subtypes, reflecting therapeutic gains over the study period. Five-year overall survival was 30.6% for HR-positive/HER2-negative, 41.3% for HR-positive/HER2-positive, 35.5% for HR-negative/HER2-positive, and 10.3% for triple-negative. Year-over-year gains were statistically significant in all subtypes except triple-negative, where outcomes remain markedly worse.
Researchers analyzed 761,471 invasive breast cancer diagnoses in the SEER 17 registry from 2010 through 2021, including 43,934 cases of distant disease at diagnosis. SEER does not capture screening adherence, obesity, alcohol use, hormone therapy, or other individual-level risk factors, so the drivers of the rise cannot be identified from these data. Recurrent metastatic disease was not included.
The parallel rise in both sexes and across subtypes points away from female-specific exposures and toward broader population-level factors. Why de novo metastatic disease is increasing despite available screening remains unexplained. Addressing it will likely require attention to screening reach, diagnostic follow-through, and disparities in access alongside continued therapeutic progress.
"This study raises concern because we don't have good answers as to why we are seeing an increase in de novo metastatic breast cancer, regardless of breast cancer subtype. While our medicines for treating metastatic breast cancer have improved dramatically in recent years, earlier-stage breast cancer is often curable, and our study highlights the need to identify the factors driving increasing incidence of advanced disease," said senior author José P. Leone, MD, medical oncologist at Dana-Farber Cancer Institute.
Source: Avila J. JAMA Netw Open. 2026 May 12. Stage IV Breast Cancer Incidence and Survival, 2010-2021