Author Insights: Mammography False Positives Briefly Boost Anxiety

Anna N. A. Tosteson, ScD, of the Dartmouth Institute for Health Policy and Clinical Practice and Norris Cotton Center at the Geisel School of Medicine at Dartmouth, and colleagues found that false-positive mammography results elevate anxiety for women only briefly. Image: Dartmouth University

Anna N. A. Tosteson, ScD, of the Dartmouth Institute for Health Policy and Clinical Practice and Norris Cotton Center at the Geisel School of Medicine at Dartmouth, and colleagues found that false-positive mammography results elevate anxiety for women only briefly. Image: Norris Cotton Cancer Center

Women who receive a false-positive result from mammography screening may briefly experience elevated levels of anxiety, but the effect soon wears off, according to an analysis published today in JAMA Internal Medicine.

The relative risks and benefits of routine mammography screening for women have been debated for decades. Last fall, the debate took on renewed urgency as the US Preventive Services Task Force announced it would revisit its existing recommendations regarding mammography. The task force’s recommendations are influential and may affect whether health plans cover mammography.

The latest study results suggest that a temporary increase in anxiety may be one adverse effect of the false positives that inevitably result from screening.

To assess how false positives affect women and their attitudes toward future screening, Anna N. A. Tosteson, ScD, of the Dartmouth Institute for Health Policy and Clinical Practice and Norris Cotton Center at the Geisel School of Medicine at Dartmouth, and colleagues analyzed survey data from more than 1000 women who participated in the Digital Mammographic Imaging Screening Trial (DMIST). They found that anxiety was higher among women who received a false-positive result than among those who did not, but this difference didn’t persist at 1 year after screening. Women who had received a false positive were more likely to plan to have future mammograms than those who did not. Women who reported higher anxiety about potential future false-positive results were more likely to express willingness to stay overnight for testing that would reduce the risk of false positives, than those who did not report such anxiety.

Tosteson discussed the findings with news@JAMA.

news@JAMA: Why did you decide to conduct this study?

Dr Tosteson: At the time, the DMIST was launched it was thought that digital mammography wouldn’t be better at detecting cancer, but we thought it would be better at reducing false positives. We wanted to be able to value false positives when assessing the cost of digital mammography.

news@JAMA: Was digital better at avoiding false positives?

Dr Tosteson: In DMIST, there was no difference [in false positives] between traditional and digital mammography screening. Other studies have found the false-positive rate is higher for some groups of women. But overall, there is not much difference between the 2 types of mammography. Now, nearly all mammograms in the United States are digital.

False positives are a fairly common experience for women participating in mammography.

news@JAMA: What did your study tell us about the effects of false positives on women?

Dr Tosteson: We found a measurable increase in personal anxiety that was time limited, but no difference in general well-being. This suggests false-positive exams cause anxiety that is time limited. This anxiety didn’t negatively influence women’s future screening preferences. That result seems to be a little surprising.

news@JAMA: How do these results compare with other studies?

Dr Tosteson: Ours was unique in that it used a measure of well-being used by economists. The measures we used were generally not cancer-related per se. Some of the studies that have found long-term anxiety after a false positive looked at cancer-specific concerns.

news@JAMA: What are the implications for physicians counseling women or for women considering mammograms?

Dr Tosteson: Women need to understand how common the false-positive mammogram experience is. We found elevated anxiety to be a time-limited effect of false-positive test results. Our study did make it clear that women would generally prefer tests not associated with false positives, but there were limits on how far they were willing to go to get such a test. The results could be a little reassuring to women.

At the same time, I think the results have some value for people doing economic evaluations of breast screening. These evaluations include the impact of mammography on quality of life. Our study showed false-positive mammograms don’t really impact quality of life in a measurable way.

news@JAMA: What do you think is the main take-home message from your results?

Dr Tosteson: With all the controversy about mammography screenings, women need to be educated about the benefits and harms. It’s going to come down to how individual women balance the harms and benefits. It does come down to a preference-sensitive decision.Our findings would certainly not make screening less cost effective for 40- to 49-year-olds, or 50- to 59-year-olds.

Higher Vitamin D Levels at Time of Breast Cancer Diagnosis Associated with Better Survival

Higher serum vitamin D levels may be associated with longer survival for women with breast cancer. (Image: mark wragg/iStock.com)

Higher serum vitamin D levels may be associated with longer survival for women with breast cancer. (Image: mark wragg/iStock.com)

Higher blood levels of vitamin D may be associated with improved survival from breast cancer, suggest new findings from study published this week in Anticancer Research.

The study, a meta-analysis of 5 studies of vitamin D (25-hydroxyvitamin D) serum concentrations obtained at the time of breast cancer diagnosis, involved a total of 4443 women who were followed-up for an average of 9 years. The women were divided into quintiles of vitamin D serum concentrations. Women in the highest vitamin D quintile (an average of 30 ng/mL) were about half as likely to die of breast cancer during the follow-up period as those in the lowest quintile (an average of 17 ng/mL), the researchers found.

There’s a biologically plausible mechanism for vitamin D’s apparent beneficial effect on breast cancer survival, the authors suggest. “Vitamin D metabolites increase communication between cells by switching on a protein that blocks aggressive cell division,” said Cedric F. Garland, DrPH, a coauthor of the study and professor in the department of Family and Preventive Medicine, University of California, San Diego School of Medicine, in a statement. As long as vitamin D receptors are present on the tumor cells (where they remain until the tumor is advanced), “tumor growth is prevented and kept from expanding its blood supply,” he explained. “This is the reason for better survival in patients whose vitamin D blood levels are high.”

Although the researchers did not study whether adding vitamin D supplements to the diet of women diagnosed with breast cancer improved survival, they did recommend such supplementation to get serum vitamin D levels into the normal range, which is between 30 ng/mL and 74 ng/mL.

Breast cancer is the most common cancer in women worldwide, with about 1.7 million new cases and a half million deaths reported in 2012. In the United States, about 234 600 new cases and about 40 000 deaths from breast cancer were reported in 2013.

Institute Identifies Evidence Gaps for Treating Bipolar Disorder in Young People and Managing a Precursor of Breast Cancer in Women

Investigators prioritized research agendas to fill the evidence gaps surrounding treatments for bipolar disorder in young people and management of ductal carcinoma in situ in women. (Image: RTimages /iStock.com)

Investigators prioritized research agendas to fill the evidence gaps surrounding treatments for bipolar disorder in young people and management of ductal carcinoma in situ in women. (Image: RTimages /iStock.com)

Treatment decisions for bipolar disorder in young people and ductal carcinoma in situ (DCIS) in women pose difficulties for physicians and patients because these diagnoses are often imprecise and the usual therapies may cause serious adverse effects. With such treatment uncertainty surrounding both conditions, investigators have created priority lists for research that would fill the evidence gaps. The research agendas appear today in the Annals of Internal Medicine.

The investigators, from the Duke University Evidence Synthesis Group, Durham, North Carolina, worked with various stakeholders, including clinical experts and patients, to identify the evidence needed to improve treatment of bipolar disorder and DCIS. The project was funded by the Patient-Centered Outcomes Research Institute, which hopes to use the findings to set prioritized research agendas. The institute was established by Congress in 2010 with a mission to fund research providing evidence-based information to enable patients, their caregivers, and clinicians to make better health care decisions.

Regarding bipolar disorder in young people, the Duke researchers noted that up to 2.7% of individuals aged 12 to 21 years have the condition, but that it can be difficult to distinguish from other disorders, such as attention-deficit/hyperactivity disorder and behavioral disorders. They also said the use of antipsychotic drugs to treat the disorder has increased significantly in the past 20 years, but the use of these drugs in adolescents and young adults remains controversial because of the paucity of population-specific data on which to base practice recommendations.

Out of 23 potential evidence gaps regarding use of antipsychotics for bipolar disorder, the researchers and stakeholders identified 10 as high priority. In descending order of priority, they are

• effectiveness of monotherapy with antipsychotics vs combination therapy with “mood-stabilizing” medications;
• effect of antipsychotics on social, academic, and occupational functioning;
• defining key patient- and family-centered outcomes;
• effectiveness of psychiatric medications other than those from the mood-stabilizing class given as adjuncts to antipsychotics;
• effectiveness of mood-stabilizing medications vs antipsychotics;
• effectiveness of antipsychotics alone vs in combination with nonpharmacologic interventions;
• adverse effects of short- and long-term antipsychotic exposure;
• effect of demographic differences on the effectiveness of antipsychotics;
• effect of socioeconomic factors on the effectiveness of antipsychotics; and
• effect of antipsychotics on core disease features immediately and in the long-term.

As for DCIS, the researchers said screening mammography has led to a dramatic increase in the diagnosis of DCIS (now 32.5 cases per 100 000 women), but much uncertainty remains about the optimal clinical response because of the lack of reliable ways to distinguish DCIS that would never become symptomatic from DCIS that is likely to progress to life-threatening invasive cancer.

Out of 30 potential research topics addressing management strategies for DCIS, the stakeholders identified 10 future research needs. They are
• developing risk-stratification models;
• comparing a management strategy of no immediate treatment (that is, observation or active surveillance) vs immediate treatment;
• understanding the influence of clinical or biological characteristics on DCIS management strategies;
• assessing the effect of different approaches to communicating the diagnosis of DCIS to patients;
• testing decision-making tools;
• assessing preoperative imaging;
• examining the effect of management strategies on comorbid conditions,
• optimizing radiation therapy;
• identifying key patient-centered outcomes; and
• assessing the effect of management strategies on incident invasive cancer.

Breast Cancer Death Rates Continue to Decline for Women From Most Racial and Ethnic Groups

Differences in socioeconomic status and access to health care are believed to play a role in differences in the rates of breast cancer death among the various racial and ethnic groups of women in the United States. (Image: mark wragg/iStockphoto.com)

Differences in socioeconomic status and access to health care are believed to play a role in differences in the rates of breast cancer death among the various racial and ethnic groups of women in the United States. (Image: mark wragg/iStockphoto.com)

Although breast cancer death rates decreased 34% from 1990 to 2010, from 33.14 per 100 000 women to 21.92 per 100 000 women, the good news is not equally shared by all racial and ethnic groups. The finding appears today in “Breast Cancer Statistics, 2013” published online in CA: A Cancer Journal for Clinicians, a publication of the American Cancer Society.

A decline in breast cancer death rates was seen in all racial and ethnic groups except American Indians/Alaska Natives and was greater among women younger than 50 years (3.1% per year from 1990 to 2010) than among those 50 years or older (1.9% per year during the same period). The declines have been attributed to both improvements in treatment and early detection.

From 2006 to 2010, black women had the highest annual breast cancer mortality rate, with 30.8 per 100 000 dying from breast cancer. Asian American/Pacific Islander women had the lowest annual breast cancer mortality rate, with 11.5 deaths per 100 000. Annual mortality rates were 22.7 per 100 000 for non-Hispanic white women, 14.8 per 100 000 for Hispanic/Latina women, and 15.5 per 100 000 for American Indian/Alaska Native women.

The authors said research suggests that racial disparities in breast cancer death rates are due in large part to differences in socioeconomic status. They noted poverty, less education, and a lack of health insurance have been associated with a greater likelihood of dying of breast cancer.

The authors also suggested that a decrease in incidence rates for estrogen receptor–negative tumors from 2006 to 2010 (the most recent 5 years of data available) may also be a factor in the falling death rate. Unlike estrogen receptor–positive tumors, which are sensitive to the hormone estrogen and which may be treated with hormone-blocking medications such as tamoxifen to help slow the tumor’s growth, estrogen receptor–negative tumors do not respond to such treatment. Estrogen receptor–negative tumors have a poorer prognosis than estrogen receptor–positive tumors, which actually increased in incidence during this time.

It is estimated that about 232 000 new cases of invasive breast cancer and almost 40 000 breast cancer deaths will occur among US women in 2013. About 8 of 10 breast cancer cases and almost 9 of 10 breast cancer deaths will occur in women aged 50 years or older.

From 2006 to 2010, breast cancer incidence rates increased slightly (0.2% per year) among black women, decreased by 0.6% per year in Hispanic women, and did not change significantly among non-Hispanic whites, Asian Americans/Pacific Islanders, or American Indians/Alaska Natives. During this time, the average annual breast cancer incidence rate was highest in non-Hispanic white women (127.3 cases per 100 000 females) and lowest for Asian Americans/Pacific Islanders (84.7 cases per 100 000).

Study Confirms Shorter Course of Radiation for Breast Cancer Is Safe and Effective After 10 Years

A shorter course of radiation for breast cancer may work  as well as a longer course after 10 years of follow-up. Photo: Varian.com

A shorter course of radiation for breast cancer may work as well as a longer course after 10 years of follow-up. Photo: Varian.com

Longer may not be better when it comes to radiation treatment for breast cancer.

For women who underwent radiation treatment after surgery and chemotherapy for breast cancer, a radiation regimen consisting of 15 treatment sessions over 3 weeks appeared to be as effective as an alternate regimen of 25 sessions over 5 weeks after a 10-year follow-up period, according to findings from a large trial released yesterday in The Lancet Oncology. This conclusion was based on the 10-year follow-up results of the UK Standardisation of Breast Radiotherapy (START) trials, 2 randomized controlled trials investigating the optimal regimen of adjuvant radiation therapy for breast cancer.

In the United Kingdom as well as in Canada, the 3-week regimen has been the standard practice in breast cancer treatment for decades. In the United States, however, the long-time standard practice has been the longer 5-week regimen, and until recently no official guidelines on the shorter regimen existed.

The 2 trials (START-A and START-B) began in the United Kingdom in 1998 and randomized more than 4000 women to receive various radiation therapy regimens. START-B looked at longer versus shorter durations of treatment. It compared a radiation regimen of 50 Gy (gray, a standardized measurement of radiation dose) divided into 25 treatment sessions or “fractions” (2 Gy per fraction) over 5 weeks with an alternate regimen of 40 Gy divided into 15 fractions (2.67 Gy per fraction) over 3 weeks. The primary end points of the START trials were local-regional relapse, defined as cancer recurrence in the breast, chest wall, or lymph nodes on the same side of the body, and local radiation-induced toxicity or “tissue effects,” as assessed by clinician examination and photographs.

In 2008, 5-year results of the START trials were published and showed that the 2 regimens were equally effective and that the 3-week regimen had fewer adverse tissue effects. Another randomized (although smaller) Canadian trial published similar results in 2010. These results solidified practice guidelines in the United Kingdom and Canada.

In the United States, the American Society of Radiation Oncology (ASTRO) released new practice guidelines in 2011 to state that the 3-week regimen may be appropriate for a specific subset of patients with early breast cancer. However, this recommendation was not strong and thus has been loosely adopted into clinical practice. The guidelines put greater emphasis on the conventional 5-week regimen, which remains widely used in practice. According to the guidelines, a major rationale for continuing to recommend the 5-week regimen was concern that the higher per-fraction radiation dose in the 3-week regimen (2.67 vs 2 Gy per fraction) may have potential “late” radiation toxicity effects that appear only after 10 or more years, such as late tissue effects, cardiovascular events, and pulmonary toxicity.

The just-released 10-year START trial results may help address these concerns. The new data essentially confirm the 5-year results: the 3-week 40-Gy regimen was just as effective as the 5-week 50-Gy regimen with respect to local-regional relapse, and it also had fewer adverse effects, although the studies focused on local tissue effects and not cardiovascular or pulmonary effects. Nonetheless, these results suggest that the 3-week 40-Gy regimen was less harmful to normal tissue and not less effective in treating cancerous tissue.

There also was an unexpected survival benefit in the group that underwent the 3-week regimen. In other words, it’s possible that the 3-week regimen may be not only equivalent to, but actually somewhat better than, the 5-week regimen. However, because survival was a secondary (and not primary) outcome in these studies, this result needs to be investigated further.

Given the immense cost and convenience benefits of a shorter radiation therapy course in breast cancer, this large follow-up study may have the potential to influence future US clinical practice patterns. On the other hand, it may not be enough to spur immediate change: a US phase 3 clinical trial investigating the same issue is currently recruiting patients, with an estimated completion date of 2020 for final data on primary outcome measures.

Author Insights: Breast Cancer Risk Increases With Long-term Use of Calcium Channel Blockers

Christopher I. Li, MD, PhD, of the Fred Hutchinson Cancer Research Center, and his colleagues found a link between breast cancer and a particular class of hypertension drugs. Image: Fred Hutchinson Cancer Research Center

Christopher I. Li, MD, PhD, of the Fred Hutchinson Cancer Research Center, and his colleagues found a link between breast cancer and a particular class of hypertension drugs. Image: Fred Hutchinson Cancer Research Center

Women who take calcium channel blockers for more than 10 years to treat hypertension are at greater risk of developing breast cancer, according to a study published today in JAMA Internal Medicine.

Most individuals who begin hypertension treatment must take it for the rest of their lives. To better understand how such long-term exposure may affect women’s health, a team of researchers from the Fred Hutchinson Cancer Research Center in Seattle conducted a population-based case-control study of women in the Seattle area aged 55 to 74 years.

The study included 880 women with invasive ductal breast cancer, 1027 with invasive lobular breast cancer, and 856 controls without cancer. Women who used calcium channel blockers for 10 years or more had a higher risk of ductal breast cancer (odds ratio [OR], 2.4; 95% CI, 1.2-4.9) and a higher risk of lobular breast cancer (OR, 2.6; 95% CI, 1.3-5.3). Taking calcium channel blockers for shorter time periods or taking another class of antihypertensive drug was not associated with having a higher breast cancer risk.

Christopher I. Li, MD, PhD, lead author and head of the Translational Research Program at Fred Hutchinson, discussed the findings with news@JAMA.

news@JAMA: What led you to look for a relationship between antihypertensives and breast cancer?

Dr Li: This is a question we’ve been interested in for some time. Several years ago, a colleague published a small study that found a relationship with calcium channel blockers. So we designed a longer-term study. Calcium channel blockers have only become more widely used over the past few decades, so this is the first time we’ve been able to look at long-term use.

news@JAMA: What do you make of the conflicting results from your study and others?

Dr Li: This is really the only one looking at long-term use. Similar to the other groups’ studies, we found no risk with short-term use. Women may need to take them for a long time to have this effect.

news@JAMA: Did you find any reason for concern with other classes of antihypertensives?

Dr Li: No, we didn’t see an increased risk with any other antihypertensives.

news@JAMA: Is there a plausible mechanism to explain this association?

Dr Li: At this point, it’s speculative. There is no confirmed biological mechanism. One potential explanation is that the body regulates apoptosis [cell death] by opening and closing calcium channels. During the process, calcium channels open up, and an influx of calcium causes the cell to become dysregulated, burst, and die. That is how the body weeds out bad cells. There is a hypothesis that taking calcium channel blockers creates an environment that allows cancer cells to thrive, but that is very speculative.

news@JAMA: What additional research is needed?

Dr Li: We need to see if this result is replicated in other populations, starting by looking at data from other studies or administrative data.

news@JAMA: What should physicians or women know about your findings?

Dr Li: I think the main thing is these are intriguing results. It’s a somewhat unexpected finding. I don’t think it should change current management of hypertension. Women shouldn’t read too much into it or change anything they are doing right now.  

Genetic Variants Could Help Direct Breast Cancer Prevention Therapy

New research could help clinicians determine which women at high risk for breast cancer would respond to preventive therapy. (Image: Mark Wragg/iStockphoto.com)

New research could help clinicians determine which women at high risk of breast cancer would respond to preventive therapy. (Image: Mark Wragg/iStockphoto.com)

Researchers have pinpointed variations in 2 genes that can help predict which women at high risk of breast cancer will respond to preventive treatment. The findings represent a major step toward personalized breast cancer prevention therapy, the study authors said.

In today’s Cancer Discovery, investigators in the United States and Japan report on DNA analyses from women at high risk of breast cancer who were taking the preventive drugs tamoxifen and raloxifene, including 592 who developed breast cancer and 1171 matched controls. All were selected from the 33 000 women in the National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 breast cancer prevention trials.

The analysis showed that certain single nucleotide polymorphisms (SNPs) in the ZNF423 gene and near the CTSO gene were more common in women who developed breast cancer during the trials than in women who remained disease free. Neither these 2 genes nor any SNPs related to them had ever been implicated in breast cancer risk or response to the preventive drugs. Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs) that block estrogen’s ability to signal breast cancer cells to multiply.

Additional analyses using breast cancer cell lines showed that in cells with certain variants of the ZNF423 and CTSO SNPs, estrogen increased the expression not only of ZNF423 and CTSO but also of BRCA1, an important breast cancer risk gene. In cells with other variants of the ZNF423 and CTSO SNPs, estrogen didn’t increase expression of the 3 genes. A healthy BRCA1 gene protects against breast cancer by repairing genetic damage, but mutated versions of the gene increase the risk of breast cancer.

When tamoxifen and raloxifene were added to the cells, those with protective variants of the ZNF423 and CTSO SNPs had expression of these genes and BRCA1, offering a possible explanation for why fewer cancers developed in women with these variations. With risky variants, the cells’ BRCA1 expression increased even in the presence of tamoxifen or raloxifene. Depending on which versions of the SNPs a woman had, her breast cancer risk while taking a SERM could vary by nearly 6-fold.

“For the first time, we discovered genetic factors that could be used to select women who should be offered the drugs for prevention,” lead author James Ingle, MD, of the Mayo Clinic in Rochester, Minnesota, said in a statement. “Also of substantial importance is that we have discovered new information on how tamoxifen and raloxifene work to prevent breast cancer.”