As October is Breast Cancer Awareness Month, this month’s column focuses on several studies in the literature about breast cancer that explore such topics as survival among people who carry the BRCA1 mutation, potential markers for response to endocrine therapy, overdiagnosis and overtreatment of women with ductal carcinoma in situ (DCIS), and mistaken perceptions among women about their personal risk of developing breast cancer.
Predictors of Survival Benefit From Endocrine Therapy
Two related studies identified potential predictors of survival benefit from endocrine therapy in women with breast cancer. Both studies were published in a recent issue of the Journal of Clinical Oncology.
The first study found that the presence of vasomotor symptoms (eg, hot flashes) and other specific adverse events (AEs) associated with endocrine therapy, especially during the first year of treatment, predicted improved disease-free survival (DFS) and overall survival (OS).1 The second study showed that women on treatment with endocrine therapy who had a reduction of more than 20% in mammographic density from baseline to the first follow-up mammogram had a 50% reduced risk of breast cancer–specific death.2
In an accompanying editorial, the authors point out that a woman may be more willing to tolerate the considerable AEs of endocrine therapy if this means she will gain a survival advantage.3
Adverse Events, Vasomotor Symptoms
A retrospective analysis of the international, randomized, phase 3 TEAM (Tamoxifen Exemestane Adjuvant Multinational) trial looked at the association between survival outcomes and specific AEs.1
The study included 9325 women with postmenopausal estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive breast cancer eligible for endocrine therapy. Participants were randomized to exemestane 25 mg once daily for 5 years or tamoxifen 20 mg once daily for 2.5 to 3 years, followed sequentially by exemestane 25 mg once daily for 2.5 to 3 years.
The specific AEs associated with endocrine therapy and which deplete or block circulating estrogens included vasomotor symptoms (hot flashes and night sweats), musculoskeletal events, and vulvovaginal symptoms (dryness/itching, discharge, painful sexual intercourse, and lack of libido).
Both DFS and OS were improved in patients with specific AEs versus those with nonspecific or no AEs. The incidences of distant metastases, relapse, and death were all reduced in patients with specific AEs. Outcomes were not related to treatment assignment.
The findings from this analysis may provide a potential biomarker of treatment efficacy. The authors stated that prospective studies are warranted “to advance the personalization of treatment strategies for patients with breast cancer.”
Reduction in Mammographic Density
According to results of a retrospective population-based case-control study in Sweden, patients taking tamoxifen who experienced a reduction in breast density of more than 20% from their baseline mammogram to their first follow-up mammogram had improved survival versus women with stable mammographic density on tamoxifen treatment.2
Study participants were 974 postmenopausal patients with breast cancer with both a baseline and follow-up mammogram. Of these women, 474 received tamoxifen and 500 did not. The authors measured mammographic density as a percentage change from baseline.
After a 15-year follow-up, 121 patients (12.4%) had died of breast cancer. Among women who had received tamoxifen, 35% of the breast cancer–associated deaths occurred in women who had had a reduction in mammographic density of 20% or more, compared with a 48% reduction in women who did not die from breast cancer. Women treated with tamoxifen who had a 20% or more reduction in mammographic density had a 50% reduced risk of death compared with women who had stable mammographic density from baseline mammogram to first follow-up mammogram. Although the relationship between density change on mammogram and survival was not statistically significant, it trended toward improved survival for those with reduced breast density.
The authors suggested that change in breast density from baseline to first follow-up mammogram in patients treated with tamoxifen could be a biomarker for response. If change in mammographic density on treatment is validated as an early marker for response to endocrine therapy, it could be a cost-effective tool for routine clinical use, the authors said.
1. Fontein DB, Seynaeve C, Hadji P, et al. Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis. J Clin Oncol. 2013;31(18):2257-2264.
2. Li J, Humphreys K, Eriksson L, et al. Mammographic density reduction is a prognostic marker of response to adjuvant tamoxifen therapy in postmenopausal patients with breast cancer. J Clin Oncol. 2013;31(18):2249-2256.
3. Henry NL, Stearns V. Treatment-emergent effects may predict benefit from endocrine therapy. J Clin Oncol. 2013;31(18):2233-2235.
DCIS Overdiagnosed and Overtreated in the United States
The increased use of screening leads to detection of more cancers that are potentially clinically insignificant, including DCIS and Barrett esophagus, according to a recent report published in the Journal of the American Medical Association.
The detection and removal of these specific precancerous lesions have not led to a lower incidence of invasive cancer, stated the authors.
The authors noted that the word cancer carries associations of “an inexorably lethal process,” but lesions like DCIS and Barrett esophagus often represent indolent diseases that will not cause harm during a patient’s lifetime if left untreated. Naming them cancers can lead to unnecessary anxiety, incorrect expectations of risk, and unnecessary treatment.
In March 2012, the National Cancer Institute (NCI) convened a meeting to evaluate the overdiagnosis of tumors that would not cause harm if left untreated. Overdiagnosis, the panel noted, necessarily often leads to overtreatment if not recognized. Overdiagnosis of indolent cancer is common and is a consequence of screening programs, they state.
A working group was formed to develop a strategy related to the current approach to cancer screening and prevention. The panel noted that an ideal screening intervention should focus on detection of diseases that are ultimately harmful and more likely to be cured if detected early. Going forward, avoiding overtreatment will require better screening programs that incorporate improved characterization of the biology of the disease detected and use disease dynamics (ie, how the disease will behave over time) as well as molecular diagnostics that can determine whether a cancer is aggressive or indolent.
The working group called for a change in cancer terminology based on companion diagnostics and avoiding the use of the word cancer for lesions that are unlikely to be lethal if left untreated. They stated that premalignant conditions such as DCIS or high-grade prostatic intraepithelial neoplasia should not be designated as cancer by name. They also recommended that molecular diagnostics that can identify indolent and low-risk lesions be adopted and validated. The working group emphasized the necessity for a new taxonomy and classification system for indolent lesions of epithelial origin (IDLE).
The creation of observational patient registries for IDLE would be useful to trace the course of these lesions over time. The data from such registries would provide a link between disease dynamics (growth rate over time) and disease diagnostics that could support the use of less invasive interventions for these lesions.
The strategies called for by the working group include reducing frequency of screening for IDLE lesions, focusing screening on high-risk populations, raising the threshold for recall and biopsy, and testing the safety and efficacy of risk-based screening approaches to help select appropriate patients for cancer screening. The goal is to detect potentially lethal lesions while avoiding detection of inconsequential disease.
The authors stated that physicians and patients should engage in open discussion about these complex issues.
Esserman LJ, Thompson IM Jr, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA. 2013;310(8):797-798.
1 in 5 Women Do Not Believe Their Breast Cancer Risk Assessment
A recent study reported that nearly 20% of women who participated in a risk-assessment study did not believe the breast cancer risk they were assigned. Most of the women who distrusted their numbers stated that they felt that the risk-assessment tool did not fully incorporate their family history of cancer or their personal health habits.
If women don’t believe their actual risk of developing breast cancer, then they cannot make informed medical decisions, stated senior author of the study Angela Fagerlin, PhD. This goes both ways—if they believe their risk is not high when it is, they might not seek chemoprevention strategies that could significantly reduce their risk; if, on the other hand, they have been assigned a low risk and they believe their risk assessment should be higher, they may seek out medically inappropriate treatments that can cause long-term problems, she explained.
The findings, which are part of a larger study that provides information about medications that can reduce risk of breast cancer, were published in Patient
Education and Counseling.
The study included 690 women at above-average risk of developing breast cancer. They completed a web-based decision aid that included questions about age, ethnicity, personal history of breast cancer, and the number of first-degree relatives with breast cancer. Based on their answers, they were assigned a 5-year risk of developing breast cancer and were given information on prevention strategies. They then were asked to recall their 5-year risk of developing breast cancer, and those who gave an incorrect answer were asked why they forgot or disagreed with the number.
Among participants, 22% who incorrectly reported their risk said that they disagreed with the numbers. The most common reason for disagreement was that their family history made them either more or less likely to develop breast cancer. Other participants believed that having no family history of breast cancer should place them in the low-risk category. One-third of women said their “gut instinct” told them that their risk numbers were either too high or too low.
Lead author of the study, Laura D. Scherer, PhD, said that fear could account for some of this distrust. Many women assumed certain factors would affect their risk, but these factors did not place them at increased risk.
Both Scherer and Fagerlin found the study results of concern, since they suggest that a proportion of women who are given a risk assessment for developing cancer will not seek the most appropriate medical care.
Scherer LD, Ubel PA, McClure J, et al. Belief in numbers: when and why women disbelieve tailored breast cancer risk specifics. Patient Educ Couns. 2013;92(2):253-259.
Similar Survival in Early BRCA1-Positive and -Negative Breast Cancer
According to a study recently published in the Journal of Clinical Oncology, patients with early-onset BRCA1-positive breast cancer have a survival rate similar to that of patients with early-onset BRCA1-negative breast cancer. Among BRCA1 mutation carriers, positive nodal status was a significant predictor of poorer survival, while oophorectomy strongly predicted improved survival.
The study enrolled 3345 women aged 50 years or younger with stage I-III invasive breast cancer diagnosed between 1996 and 2006. Only patients with a first primary cancer were included.
Of the 3345 enrollees, 233 (7%) carried a BRCA1 mutation. Mutation carriers were diagnosed at an earlier age than noncarriers (42 years vs 44 years, respectively; P <.001) and were significantly less likely to be estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and HER2-positive (P <.001 for all 3 comparisons) but significantly more likely to have triple-negative disease (69% vs 13%, respectively; P <.001) and more likely to have undergone oophorectomy (50% vs 14%, respectively), with most having the procedure following their diagnosis of breast cancer.
At a mean follow-up of 7.4 years, the 10-year survival rate was 80.9% for mutation carriers and 82.2% for noncarriers. Among the 485 women with triple-negative breast cancer, overall survival was not inferior among carriers versus noncarriers.
Among BRCA1 mutation carriers, lymph node status was highly predictive of survival, with positive nodal status associated with significantly lower 10-year survival (P <.001). Overall, as well as in carriers, survival was similar in women with tumors 0.1 to 1.0 cm and 1.1 to 2 cm. The 10-year survival rate among carriers with small (<2 cm) breast tumors was 89.9% for node-negative patients and 68.6% for node-positive patients. Among carriers with breast tumors ≤1 cm, 27.5% were node positive, and their 10-year survival rate was 81.1%.
Of the 233 BRCA1-positive patients, 101 (43.6%) were deemed high risk (node positive or tumors >5 cm), and their survival was 68.2% at 10 years.
Oophorectomy had a positive effect on prognosis among carriers, and to a smaller extent, in noncarriers.
“Oophorectomy in BRCA1 carriers is beneficial for reducing death after breast cancer. The reduction in death is largely for those occurring as a result of breast cancer, but a number of avoidable deaths will be from secondary primary ovarian cancers,” wrote the authors.
“If these observations are replicated in other populations, oophorectomy should be considered a standard of care for women with breast cancer and a BRCA1 mutation,” they said.
Chemotherapy improved survival among carriers compared with no chemotherapy, even though the tumors of those treated with chemotherapy tended to be larger, node positive, and ER negative.
Huzarski T, Byrski T, Gronwald J, et al. Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. J Clin Oncol. 2013;31(26):3191-3196.