Metastatic breast cancer treatments have aided decline in deaths

Nearly one-third of the decrease (29%) is due to advances in treating metastatic breast cancer -- a form that has spread to other areas of in the body and is known as stage 4 breast cancer or recurrent cancer. Although these advanced cancers are not considered curable, women with metastatic disease are living longer than ever.

The analysis helps cancer researchers assess where to focus future efforts and resources.

"We've known that deaths from breast cancer have been decreasing over the past several decades, but it's been difficult or impossible to quantify which of our interventions have been most successful, and to what extent," said Jennifer Caswell-Jin, MD, assistant professor of medicine. "This type of study allows us to see which of our efforts are having the most impact and where we still need to improve."

Caswell-Jin and Liyang Sun are co-first authors of the study, which was published Jan. 16 in the Journal of the American Medical Association. Sylvia Plevritis, PhD, professor and chair of biomedical data science, and Allison Kurian, MD, MSc, professor of medicine and of epidemiology and population health, are co-senior authors.

The study was a collaborative effort by a national consortium of researchers called CISNET, or the Cancer Intervention and Surveillance Modeling Network. CISNET was established in 2000 by the National Cancer Institute to understand the impact of cancer surveillance, screening and treatment on incidence and mortality. Doing so requires sophisticated computer algorithms capable of modeling the natural course of the disease and the typical treatment paths of individual patients, then translating that information to population-level data collected by the national Surveillance, Epidemiology, and End Results Program, or SEER registry, from 1975 to 2019.

The study is the third in a trio of papers from CISNET published since 2005 that assess the relative contributions of regular screening and treatment advances on breast cancer deaths. The previous two papers informed national guidelines and helped cancer researchers focus their efforts on the most intractable problems.

"Twenty years ago, there was a question whether routine screening mammography actually decreased the number of deaths from breast cancer," Plevritis said. But in 2005, she and other CISNET researchers published a paper in the New England Journal of Medicine that conclusively demonstrated that screening was responsible for anywhere from 28% to 65% (different models came up with varying degrees of impact) of the reduction in mortality by 2000 between 1975 and 2000.

The second paper, published in 2018 in the Journal of the American Medical Association, highlighted the differences in treatment responsiveness and survival outcomes among women with differing breast cancer subtypes from 2000 to 2012 -- pinpointing subgroups with poorer survival.

"We found that, while screening still had an important impact, most of the decline in annual deaths was due to improvements in treating early-stage breast cancer based on each cancer's molecular profile," Plevritis said.

The current study is the first to explicitly include patients with metastatic breast cancer in its models. The finding that 29% of the decrease in mortality is due to advances in treating metastatic breast cancer both surprised and gratified the researchers.

"Initially, we assumed that treatment of advanced disease was unlikely to make a significant contribution to the declines in mortality we documented in the previous two papers," Caswell-Jin said. "But our treatments have improved, and it's clear that they are having a significant impact on annual mortality."

The CISNET researchers used four computer models to assess the SEER data from 1975 to 2019 -- one developed at Stanford Medicine in the Plevritis Lab, one by researchers at the Dana-Farber Cancer Institute, one at MD Anderson Cancer Center, and another jointly developed by researchers at the University of Wisconsin and Harvard Medical School. The four models came up with remarkably similar estimates for the impact of each intervention: screening mammography, treatment of early-stage (stages 1, 2 or 3) breast cancer and treatment of metastatic breast cancer.

The models reproduced the decline in mortality in breast cancer known from SEER data, from 48 per 100,000 women dying of breast cancer each year in 1975 to 27 per 100,000 in 2019 -- a decrease of about 44%. The models arrived at a larger estimated reduction in mortality of about 58% because the incidence of breast cancer has risen during the same period and more women would have died had screening and treatments not improved.

The models concluded that about 47% of this reduction in mortality is the result of improved treatments for early-stage breast cancer, and about 25% is attributed to screening mammography. The remainder, or about 29%, is due to improvements in treating metastatic disease.

"Designing the new model, which had to account for individuals with non-metastatic cancer who underwent treatment but later progressed to metastatic cancer, and who may have been treated with multiple drugs over the course of their disease, was extremely complex," Plevritis said. "It took about four years. But it was really satisfying when we were able to validate the model's behavior and see that all four models from different institutions, which used the new model inputs in different ways, delivered consistent findings. The models not only make sense, but also produce meaningful insights."

The impact of treating metastatic disease is exemplified by the increases in median survival time after metastasis: Patients diagnosed in 2000 with metastatic disease lived an average of 1.9 years versus an average of 3.2 years for those diagnosed in 2019. Survival time varies by subgroup status, however. Patients with what are known as estrogen receptor-positive and HER2 positive cancers saw an average increase in survival time of 2.5 years. Those with estrogen receptor-positive and HER2-negative cancers lived an average of 1.6 years longer, but those with cancers that are estrogen receptor-negative and HER2-negative lived about 0.5 years longer in 2019 than in 2000.

"It was meaningful as a breast oncologist to spend time with this history and see real progress over the past decades," Caswell-Jin said. "There is much more work to be done; metastatic breast cancer isn't yet curable. But it is rewarding to see that advances have made a difference in these numbers," she added. "Our scientific and clinical work is helping our patients live longer, and I believe deaths from breast cancer will continue to steadily decline as innovation continues to grow."

Researchers from MD Anderson Cancer Center, the Dana-Farber Cancer Institute, the University of Wisconsin-Madison School of Medicine and Public Health, the National Institutes of Health, the Albert Einstein College of Medicine, Harvard Medical School, Georgetown University, and the Georgetown-Lombardi Institute for Cancer and Aging contributed to the study.

The study was funded by the National Institutes of Health (grants U01CA253911 and U01CA199218).