During the same period, there was no increase in advanced disease in older women, according to the researchers, led by Rebecca H. Johnson, MD, from the Seattle Children’s Hospital and the University of Washington.

In the young women, the incidence of breast cancer with distant involvement at diagnosis increased from 1.53 per 100,000 women in 1976 to 2.90 per 100,000 women in 2009. This is an absolute difference of 1.37 per 100,000, and is an average compounded increase of 2.07% per year (P < .001) over a 34-year interval.

The findings come from an analysis of incidence trends from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database.

The findings could foretell an ominous future. “The trend shows no evidence for abatement and may indicate increasing epidemiologic and clinical significance,” the researchers write.

However, experts contacted by Medscape Medical News did not sound any alarms; in fact, they suggested that the study evidence is not strong.

“These are small changes over long periods of time and without corroboration by other large population datasets. It is difficult to draw many conclusions [about the findings],” said Julie Margenthaler, MD, a surgical oncologist from the Siteman Cancer Center and the Washington University School of Medicine in St. Louis, Missouri.

Another expert said the study findings are somewhat puzzling.

It is not clear from the study “whether the overall rate of breast cancer in young women is actually increasing,” said Ann Partridge, MD, a medical oncologist from the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts. In other words, the study does not indicate whether the increase in advanced disease means that there is an overall increase in disease in young women.

That is important because other studies using SEER data have indicated that the rate of overall disease is stable in young women, said Dr. Partridge.

She pointed out that Dr. Johnson and colleagues found that the rates of localized and regional disease held steady in young women. Therefore, because they found an increase in advanced disease, there should be an overall increase in young women, she said.

However, the researchers “did not show/discuss data on overall rates of breast cancer in young women,” Dr. Partridge wrote in an email. This omission, combined with the fact that the study findings might be in conflict with findings from other studies using SEER data, “leads me to wonder about the article,” she said.

Study statistician Franklin Chien, from Seattle Children’s Hospital, explained to Medscape Medical News how the seemingly contradictory statistics play out.

True, he said, there was no statistically significant increase in breast cancer in younger women overall, just younger women with advanced disease. “It is relatively rare for women to present with distant disease at diagnosis…. This is why we can see such a marked trend in distant-disease breast cancer, but not in breast cancer in young women as a whole,” he explained in an email.

Why the Increase?

The researchers decided to undertake this study in part because there is a “clinical impression” that more young women are being diagnosed with advanced breast cancer.

A clinician not involved with the study shares that impression.

“Anecdotally, we seem to be seeing a lot more younger women with breast cancers, many of whom are advanced. However, I have no data to support this,” Kathryn Evers, MD, told Medscape Medical News. She is a radiologist who specializes in breast cancer at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

The researchers sought proof of this clinical impression using 3 of the regional SEER registries. They culled data on incidence, incidence trends, and survival rates as a function of age and extent of disease at diagnosis for 3 periods: 1973 to 2009, 1992 to 2009, and 2000 to 2009.

In the SEER registries, localized disease is defined as being confined to the breast, regional is defined as contiguous and adjacent organ spread (lymph nodes, chest wall), and distant is defined as remote metastases (e.g., bone, brain, lung).

The researchers found that breast cancer rates, expressed by the annual percent change (APC) in incidence, were stable over the study period — except in 2 groups.

“APCs increased significantly (P < .01 and APC > 2.0) in, and only in, women aged 25 to 39 years with distant disease at diagnosis,” they write. The “one exception” to this finding is “older women, who had an increase in localized disease associated with implementation of screening mammography during the 1980s.”

Table. Increase in APC Over the 3 Study Periods in Women 25 to 39 Years of Age

The   category of distant disease as a proportion of all invasive breast cancer in younger women increased from 4.4% in the 1970s, to 4.8% in the 1980s, 5.5% in the 1990s, and 7.2% in the 2000s, the researchers report.

“Why is the increase occurring?” they ask. A possible answer is the “increased diagnostic sensitivity and scrutiny,” they say.

But if sensitivity is responsible, then there would be an “increase in detection in all patients,” Dr. Partridge pointed out.

Dr. Evers thinks that increased scrutiny is “possible” because “when breast cancer is diagnosed in younger women, there is an emotional response on the part of the physicians, so they want to ‘do everything’.” However, that “is probably a pretty small effect; most women get a pretty complete evaluation once they get the diagnosis,” she noted.

It is also possible that diagnosis is “delayed more frequently than in older women,” she added.

Dr. Margenthaler also believes delayed diagnosis could play a role in the findings. “The typical scenario is that a young woman feels a lump, which prompts her presentation. [However], by the time a lump is felt, it is already on average much larger than a cancer found by screening mammogram,” she explained.

Dr. Partridge said that it is “possible that something is going on biologically,” but she also said that there is “limited biologic rationale for this.”

Dr. Johnson and colleagues offer no biologically based theories about their findings.

However, the researchers and all of the experts interviewed by Medscape Medical News agree that younger women tend to be diagnosed with more aggressive and advanced disease than their older counterparts.

Last year, Dr. Partridge and colleagues published a retrospective study of 22,000 women with breast cancer to elucidate the relation between age and disease stage (Oncologist. 2012;17:775-782).

They found that being younger than 40 years is “only modestly associated with higher stage disease.” They also found that presenting with “symptoms” strongly predicted higher stage, which was more common in the younger women. “Most breast cancer in young women is picked up by a sign or symptom — usually a breast symptom, such as a mass,” said Dr. Partridge. If medical practitioners want to see fewer young women present with advance disease, research is needed to learn how practitioners and women can better recognize early symptoms of breast cancer, they conclude.

Dr. Johnson reports being on the board of the Young Adult Cancer Alliance. Coauthor Archie Bleyer, MD, from the Oregon Health and Sciences University in Portland, reports having financial ties to Sigma-Tau Pharmaceuticals. Dr. Margenthaler, Dr. Partridge, and Dr. Evers have disclosed no relevant financial relationships.

The combination of the biologic lapatinib (Tykerb) and capecitabine (Xeloda) chemotherapy appears to shrink brain metastases from HER2-positive breast cancer without need for radiation, a phase II trial showed.

Two-thirds of patients saw their previously-untreated brain lesions shrink by at least half with the treatment regimen, Thomas Bachelot, MD, of the Centre Léon Bérard in Lyon, France, and colleagues found in the LANDSCAPE trial.

The median time to whole-brain radiotherapy (WBRT) was 8.3 months, the group reported online in the Lancet Oncology.

“Traditionally, most of these women receive WBRT which can impair cognitive function. Delaying such a treatment for those patients is potentially a big advance, which is particularly relevant for a population with short overall survival,” Bachelot noted in a press release.

The efficacy of lapatinib and capecitabine was similar to whole-brain radiotherapy, noted Rupert Bartsch, MD, and Matthias Preusser, MD, both of the Medical University of Vienna, in an accompanying commentary.

The primary systemic strategy “might already be a valid treatment option” in this population with minimal clinical symptoms and good performance status, they suggested.

However, they cautioned about limitations of the treatment and the study.

Serious adverse events weren’t uncommon with lapatinib plus capecitabine — 49% of the women faced grade 3 or 4 adverse events, most commonly diarrhea and hand-foot syndrome.

Side effects were “manageable,” however, compared with those of brain radiation, which include delayed side effects of cerebellar dysfunction and cataracts, according to the researchers. Only four of the women discontinued treatment because of adverse effects.

But the group provided no data on neurocognitive function in the open-label, single-arm study of 45 patients.

“Furthermore, more than 40% of all patients did not present with neurological symptoms at baseline, which raises the question of whether screening for brain metastases was done and raises doubts about the feasibility of extrapolation of their findings to the general population of patients with symptomatic brain metastases,” Bartsch and Preusser pointed out.

“More than 95% of all patients presented with Eastern Cooperative Oncology Group performance status of 0–2, which is better than would be expected in an unselected population of patients with brain metastases.”

Nevertheless, it’s clear that a phase III study is warranted, they agreed with the researchers, who said they are planning such a trial.

The brain metastasis response was “much higher than we expected” and greater than the 27% to 50% response rates seen with whole-brain radiotherapy alone in prior studies, Bachelot’s group noted.

For the primary endpoint, 29 of the 44 evaluable patients had an objective CNS response marked by at least 50% volume reduction of brain metastases, all partial responses.

Notably, nine of the women (20%) got a CNS volumetric reduction of 80% or greater. Median time to CNS progression was 5.5 months.

The researchers cautioned that direct comparison cannot be made between these results and those of whole-brain radiation alone or other regimens, such as monotherapy.

The study was funded by GlaxoSmithKline-France and UNICANCER.

Bachelot and another co-author reported consultant or advisory roles at GlaxoSmithKline-France and research funding by GlaxoSmithKline-France. A third author declared research funding by GlaxoSmithKline-France.

Bartsch and Preusser reported having no conflicts of interest to disclose.

Primary source: The Lancet Oncology
Source reference:
Bachelot T, et al “Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study” Lancet Oncol 2012; DOI: 10.1016/S1470-2045(12)70432-1.

Additional source: The Lancet Oncology
Source reference:
Bartsch R, Preusser M “Primary systemic treatment of breast-cancer brain metastases” Lancet Oncol 2012; DOI: 10.1016/S1470-2045(12)70449-7.