New Data on Prognostic Factors, Disease Detection, Drug Toxicities, and Treatment Adherence Presented at SABCS
The San Antonio Breast Cancer Symposium (SABCS) offers state-of-the-art information on all aspects of breast cancer biology, diagnosis, and treatment, drawing an international audience of more than 7,500 physicians, researchers, and other health-care professionals from over 90 countries. Through our print issues, online reports, and video Newsreels, The ASCO Post has reported on dozens of studies presented at the recent symposium (visit ASCOPost.com). Here we offer additional noteworthy meeting highlights.
Circulating Tumor Cells in the Neoadjuvant Setting
Francois-Clement Bidard, MD, PhD
Circulating tumor cell levels could be prognostic in the neoadjuvant setting, according to the international IMENEO meta-analysis in early breast cancer patients.1 “Postneoadjuvant survival does not rely exclusively on breast cancer characteristics and pathologic complete response. Circulating tumor cells complement, but do not duplicate, the usual prognostic factors,” said Francois-Clement Bidard, MD, PhD, of the Institut Curie in Paris, who presented the findings.
Specifically, circulating tumor cells exerted a “number-dependent” impact on overall survival, distant disease-free survival, and locoregional relapse-free interval. “Each circulating tumor cell adds a further quantum of bad prognosis,” commented Dr Bidard, the prognostic effect being significant starting from a threshold of ≥ 2 circulating tumor cells per 7.5 mL blood.
Circulating tumor cells, considered the “seeds” of distant metastases, can be identified in blood with the U.S. Food and Drug Administration (FDA)-cleared CellSearch system. Although circulating tumor cells have been shown to be prognostic before and during therapy in patients with metastatic disease, and before adjuvant therapy for nonmetastatic disease, their meaning in the neoadjuvant setting has been less clear, he said.
Researchers obtained data on 2,156 patients from 16 centers; circulating tumor cell data was collected from patients either before the start of neoadjuvant chemotherapy or before surgery. Circulating tumor cell counts significantly decreased during neoadjuvant chemotherapy (P < .0001). Their magnitude was not significantly associated with the achievement of pathologic complete response but was linked to other outcomes, as determined by a multivariate analysis.
Clinical Breast Exam Remains Important
Clinical breast examination still has a place in detecting breast cancer in the primary care setting, especially in older patients, according to investigators from the Swedish Cancer Institute in Seattle, who found that physician-detected cancers had high-risk characteristics.2
We have manual methods of detection that should be included. It’s completely wrong not to [physically] examine the breasts.— Judith A. Malmgren, PhD
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“We have manual methods of detection that should be included. It’s completely wrong not to [physically] examine the breasts,” said Judith A. Malmgren, PhD, who led the study.
The American Cancer Society no longer recommends clinical breast exam as part of a routine or annual physical examination. The U.S. Preventive Services Task Force has not issued guidelines on its use, stating that the evidence is insufficient.
Dr. Malmgren and her team conducted a retrospective cohort study of three methods for detecting breast cancer of all stages. The subjects were 12,049 women from their dedicated institutional breast cancer registry spanning from 1990 to 2014. The researchers compared the diagnostic characteristics and disease-specific survival for patients in each of three categories of detection:
- Physician or health-care professional detection of a palpable lump or abnormality at routine examination that prompted a workup resulting in a breast cancer diagnosis
- Patient detection of breast symptoms, such as a palpable lump, pain, swelling, or bleeding, that prompted a doctor’s visit and subsequent breast cancer diagnosis
- Mammographically detected disease found on routine mammography in the absence of complaints or known physical findings
Over time, 5% of breast cancers (n = 641) were physician detected, 38% (n = 4,556) were patient-detected, and 57% (n = 6,852) were mammography-detected. The percentage of cancers detected by physicians decreased from 9% in 1990 to 3% in 2013 as the relative percentage of mammography-detected cancers increased. The annual number of physician-detected cancers remained fairly constant at 20 to 40 per year.
There were some significant differences in cancers detected by physicians. They included greater percentages of women aged 75 and older (15%), higher-stage (stage II–IV) tumors (56%), hormone receptor–negative tumors (15%), and triple-negative cancers (11%) (all P < .001). Physician-detected cancers were also less likely to be ductal and more likely to be lobular than the others, Dr. Malmgren reported.
“Physicians detected more invasive cancers and more stage IV tumors, and they were incidental findings in women who came in to see them for another reason,” she said, emphasizing that clinical breast examination should not be discarded. “It’s also important to note that 21% of the physician-detected cancers were not seen on subsequent mammography, nor were 17% of patient-detected ones,” she said.
Overall, 5-year disease-specific survival was high for all groups; it was best for mammography-detected cases (98%), followed by physician-detected cases (95%) and then patient-detected cases (92%).
Aromatase Inhibitors Reduce Endothelial Function
Aromatase inhibitors were associated with endothelial dysfunction in a cross-sectional study of women with breast cancer taking aromatase inhibitors compared with healthy controls.3 Endothelial dysfunction is a known predictor of cardiovascular disease risk, and results suggest that oncologists should examine cardiac function and address cardiac risk factors in women who are candidates for these drugs.
Most women with breast cancer are at greater risk of dying from cardiovascular disease than from breast cancer. The cardiovascular risk of aromatase inhibitors has always been a concern.— Anne H. Blaes, MD
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“Aromatase inhibitors reduce the risk of breast cancer-related mortality in women with operable estrogen receptor–positive breast cancer. Because these women are living longer, it is important to understand the long-term complications so we can weigh the potential benefits vs risks,” said lead author Anne H. Blaes, MD, Masonic Cancer Center, University of Minnesota, Minneapolis. “Most women with breast cancer are at greater risk of dying from cardiovascular disease than from breast cancer. The cardiovascular risk of aromatase inhibitors has always been a concern.”
Endothelial dysfunction detected by EndoPAT, an FDA-approved device for noninvasive endothelial function assessment, is independently associated with an increased risk of cardiac events. The present study compared endothelial function in 25 healthy postmenopausal women with 36 postmenopausal women with locally advanced breast cancer who were prescribed an aromatase inhibitor. A total of 20 healthy women and 36 women with breast cancer (mainly stage I and II treated with curative intent) were included in the final analysis. Women with a history of cardiac risk factors, such as tobacco use, hypertension, and hyperlipidemia, were excluded.
All subjects underwent testing to examine several components of endothelial function, including biomarker analysis, pulse wave analysis using the HDI/Pulse Wave CR-2000 Cardiovascular Profiling System (not cleared for marketing by the FDA), and pulse contour analysis using the EndoPAT 2000 system.
The EndoPAT ratio showed a decrease in endothelial function in breast cancer patients compared with controls: 0.8 vs 2.6, a statistically significant difference (P < .0001). The difference remained significant after adjusting for systolic blood pressure.
No association was observed between vascular function and cancer treatment characteristics.
“Other studies suggest that cardiovascular risk is even greater in women with preexisting cardiovascular disease who are taking aromatase inhibitors. We need better biomarkers to predict cardiovascular disease risk on chronic aromatase inhibitor therapy, and we need to take cardiac function into consideration when we prescribe aromatase inhibitors,” Dr. Blaes said.
Dr. Blaes said that the study is limited by its small size, and further research is needed to confirm these findings.
C. Kent Osborne, MD
“This is preliminary evidence. This adds to our knowledge that low estrogen levels can have adverse effects on cardiovascular function. We are not saying women with early-stage, postmenopausal, estrogen receptor–positive breast cancer should not take aromatase inhibitors. But we need to consider and address all other cardiac risk factors,” said C. Kent Osborne, MD, Director of the Dan L. Duncan Comprehensive Cancer Center at Baylor University in Houston. Dr. Osborne moderated a press conference where these data were discussed.
Symptoms Affect Adherence to Hormonal Therapy
Women who experienced menopausal symptoms that included nausea, vomiting, and headaches were significantly less likely to be adherent to assigned medication 4.5 years after starting treatment, according to an assessment of data from the International Breast Cancer Intervention Study I (IBIS-I),4 a large, placebo-controlled, randomized trial whose first results were published in 2002.5 The 3,987 UK women included in IBIS-I were at high risk for developing breast cancer.
Samuel G. Smith, PhD
Lead author of the current study, Samuel G. Smith, PhD, Cancer Research UK postdoctoral fellow and university academic fellow at the University of Leeds, emphasized that 5 years of tamoxifen is known to reduce the risk of breast cancer by at least 30% in at-risk women, and the effect persists for at least 20 years. “However, the effectiveness of tamoxifen is dependent on its appropriate use for the full duration of therapy,” he said.
Adherence to assigned medication at 4.5 years was as follows: 71.5% for placebo vs 62.1% for tamoxifen. Symptoms reported in all women were nausea/vomiting (5%), headaches (7%), hot flashes (31.5%), and gynecologic symptoms that included vaginal dryness and irregular bleeding (13.8%).
Women reporting nausea/vomiting were 82% and 84% more likely to be nonadherent to placebo and tamoxifen, respectively, compared with women who did not report these symptoms. Headaches were more likely to be associated with nonadherence only in the placebo group, where women with these symptoms were 70% more likely to be nonadherent. Gynecologic symptoms were significantly associated with adherence in the tamoxifen arm only, and women with these symptoms were 30% more likely to be nonadherent.
An interesting finding of the study is that the association between adherence and menopausal symptoms was observed in both the placebo and active-therapy arms. “This suggests that women may be attributing naturally occurring menopausal symptoms to the medication they are taking. Therefore, we need to find new and innovative ways of supporting women who experience these symptoms,” Dr. Smith said.
At a press conference where this study was discussed, breast cancer experts agreed that these findings have implications for all women considering preventive hormonal therapy, whether it is tamoxifen or an aromatase inhibitor. They concurred that it is important to communicate risks and benefits clearly to women prior to initiating therapy and to manage expectations by providing realistic and accurate information about side effects as well as expected benefits. ■
Disclosure: Drs. Blaes, Bidard, Osborne, and Smith reported no potential conflicts of interest. Dr. Malmgren reported that her study was funded by the Kaplan Cancer Research Fund.
1. Bidard FC, Michiels S, Mueller V, et al: International meta-analysis of circulating tumor cell detection in early breast cancer patients treated with neoadjuvant chemotherapy (IMENEO study). 2016 San Antonio Breast Cancer Symposium. Abstract S3-01. Presented December 8, 2016.
3. Blaes AH, Beckwith H, Hebbel R, et al: Aromatase inhibitors and endothelial function: Is there an association with early cardiovascular disease? 2016 San Antonio Breast Cancer Symposium. Abstract S5-07. Presented December 9, 2016.
4. Smith SG, Sestak I, Howell A, et al: Menopausal symptoms as predictors of long-term adherence in the International Breast Cancer Intervention Study I (IBIS-I). 2016 San Antonio Breast Cancer Symposium. Abstract S5-03. Presented December 9, 2016.