More breast cancer lesions were diagnosed in women with dense breasts when ultrasound screening was conducted in conjunction with mammography compared with mammography alone, according to a study presented at the San Antonio Breast Cancer Symposium (SABCS) 2014.

&ldquo;We found that among women with dense breasts, screening breast ultrasonography detected a significant number of breast cancers not discovered by mammography,&rdquo; Jean M. Weigert, MD, of the Hospital of Central Connecticut, New Britain, explained.

According to the Radiological Society of North America, mammography is considered the best single modality for population-based screening, but its sensitivity is diminished by up to 20% in patients with dense breasts, due in most part to masking, a phenomenon in which surrounding dense breast tissue obscures a cancer on mammography.

Four years of ultrasound data from 2 sites (5 offices) in Connecticut were included in the analysis presented at SABCS. A retrospective analysis of data from these sites was conducted from 2009 to 2013 by Weigert and colleagues. Approximately 30,000 screening mammograms were included for each year in patients ranging in age from 45 to 77 years.

A total of 46 cancers or high-risk lesions not visible on screening mammography were identified by ultrasound, ranging in size from 0.3 to 8.0 centimeters. These lesions were not palpable, and most patients did not have additional risk factors other than dense breasts. Four patients had positive metastatic lymph nodes.

The number of breast ultrasounds conducted for dense breasts was 2706 in year 1, 3351 in year 2, 4128 in year 3, and 3331 in year 4. Ultrasonography detected between 11 and 13 breast cancers per year during this 4-year period, representing between 3 and 4 breast cancers per 1000 women screened. During years 3 and 4, cancers were found in patients who had a prior ultrasound screening, although their mammograms remained negative. These cancers were small and node negative.

The positive predictive value (the proportion of women with breast cancer among those with a positive breast ultrasound result) improved over the 4-year period. In year 1, the positive predictive value was 7.1%; in year 4, it was 17.2%.

&ldquo;The positive predictive value for mammography is about 20% to 30%, and we are getting close to that with breast ultrasonography now that we are more experienced,&rdquo; Weigert said. &ldquo;Without the additional screening, we do not know at what point these lesions diagnosed with screening breast ultrasonography would have been clinically evident, either on mammography or physical examination. Of concern, the number of eligible women who elect to undergo the additional test remains low, at about 30%, which is due to several factors, including education and cost.&rdquo;

Beginning in 2009, legislation mandated that patients undergoing mammography in Connecticut be informed that further screening may be of benefit if they have dense breasts.

In California, which enacted mandatory reporting in 2013, the law requires that patients with dense breast tissue on screening mammography receive notification in writing, with advice on discussing their screening options with their primary physician. Approximately 50% of women undergoing screening mammography are classified as having either &ldquo;heterogeneously dense&rdquo; or &ldquo;extremely dense&rdquo; breasts. In California alone, this could mean 2 million notification letters a year, and a significant increase in supplementary screening with magnetic resonance imaging and ultrasound.

According to Jafi A. Lipson, MD, of the California Breast Density Information Group (CBDIG), while studies do show that additional cancers are found with supplementary screening breast ultrasound, &ldquo;this is at the price of a large number of benign breast biopsies.&rdquo;

More breast cancer lesions were diagnosed in women with dense breasts when ultrasound screening was conducted in conjunction with mammography compared with mammography alone.

Retrospective analysis included 4 years of ultrasound data and approximately 30,000 screening mammograms per year from 2 sites in Connecticut.

A total of 46 cancers or high-risk lesions not visible on screening mammography were identified by ultrasound; the lesions were not palpable, and most patients did not have additional risk factors other than dense breasts.

The positive predictive value of breast ultrasound improved over the study period (7.1% and 17.2% in years 1 and 4, respectively).

He added that &ldquo;supplemental screening of the approximately 40 percent of California women with heterogeneously dense breasts would result in very substantial additional cost to the healthcare system. There also is concern that the increased use of supplementary screening will ultimately expose some patients to more harm, in the form of false-positive results, than good.&rdquo;

The CBDIG offers a website designed to provide information about breast density, breast cancer risk assessment, and supplementary imaging.

A recent study on the prevalence of mammographically dense breasts in the United States5 indicated that more than 25 million women who would typically undergo breast screening fall into this category. The authors, led by Brian L. Sprague, PhD, with the University of Vermont, Burlington, recommend that &ldquo;policymakers and healthcare providers should consider this large prevalence when debating breast density notification legislation and designing strategies to ensure that women who are notified have opportunities to evaluate breast cancer risk and discuss and pursue supplemental screening options if deemed appropriate.&rdquo;

Weigert JM. The Connecticut experiment: 4 years of screening women with dense breasts with bilateral ultrasound. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract [S5-01].

Experts take on challenge of breast density notification laws [news release]. Oakbrook, IL: Radiologic Society of North America. http://www2.rsna.org/timssnet/media/pressreleases/pr_target.cfm?ID=691. Accessed December 16, 2014.

California Breast Density Information Group. Frequently asked questions about breast density, breast cancer risk, and the breast density notification law in California: a consensus document. www.breastdensity.info. Accessed December 16, 2014.

Price ER, Hargreaves J, Lipson JA, et al. The California breast density information group: a collaborative response to the issues of breast density, breast cancer risk, and breast density notification legislation.

Sprague BL, Gangnon RE, Burt V, et al. Prevalence of mammographically dense breasts in the United States.

Articles

Clinical Articles

Breast Ultrasound Added to Mammography Increases Cancer Detection

An international team of investigators is evaluating the novel topoisomerase-1 inhibitor etirinotecan pegol in patients with metastatic breast cancer, and at the same time evaluating target-specific biomarkers in circulating tumor cells (CTCs). The experimental agent and the novel CTC isolation technique were described at the 2014 San Antonio Breast Cancer Symposium by Edith Perez, MD, of the Mayo Clinic in Jacksonville, Florida.

Etirinotecan pegol is a long-acting topoisomerase-1 inhibitor designed for prolonged tumor cell exposure. Topoisomerase 1 is a nuclear enzyme that plays an essential role in DNA replication, transcription, recombination, and repair. .

&ldquo;Etirinotecan pegol target-specific pharmacodynamic biomarkers will be measured in CTCs isolated from patients participating in the BEACON trial,&rdquo; Perez said. The researchers will analyze CTC information obtained at baseline and throughout treatment, and correlate these findings with clinical outcomes, she explained. .

Describing the new compound, Perez noted that the use of the parent compound irinotecan is mostly limited in the United States to colorectal cancer, although it enjoys broader use in Japan. About 10 years ago, Perez led a study of irinotecan in metastatic breast cancer where the response rate was 23%, convincing her that a topoisomerase-1 inhibitor could be useful in breast cancer.

&ldquo;Nektar Therapeutics has developed a better formulation, a pegylated formulation with a very improved pharmacokinetic profile,&rdquo; Perez said in an interview. &ldquo;Instead of high peak levels, like the parent compound produced, etirinotecan pegol produces steady levels of drug so we can expose the tumor cells to continuous levels of the active metabolite [SN38].&rdquo; .

In a previous phase II trial of 70 patients, the response rate to etirinotecan was 29%, median progression-free survival was 4.7 months, and median overall survival was 10.3 months.2 .

These encouraging results led to the phase III BEACON study, which is comparing single-agent etirinotecan to physicians&rsquo; choice of treatment in 852 previously treated patients. Topline results are expected in the first quarter of 2015, according to Perez. .

&ldquo;We mandated prior treatment with an anthracycline, a taxane, and capecitabine, which means these are truly refractory patients,&rdquo; Perez said. &ldquo;And our primary endpoint is overall survival, because we feel we owe it to our patients to strive for an overall survival benefit in our studies. Based on phase II results, we feel we can meet this endpoint.&rdquo;

Isolation of CTCs via New Technique The study is designed to isolate CTCs and examine them, both for their numbers and for target-specific pharmacodynamic biomarkers. Circulating tumor cells are shed from the tumor and circulate in the peripheral blood. The isolation of CTCs represents an attractive minimally-invasive alternative to tumor biopsies.

BEACON is employing the ApoStream&reg; system for CTC isolation. This technique, which is based on dielectrophoresis and microfluidic technology and is antibody-independent, yields higher numbers of CTCs than the first-generation EpCAM-dependent methods. Patients will be sampled at baseline, before cycle 2, before cycle 4, and at the end of treatment. Changes in these markers will be correlated with tumor response.

&ldquo;We have as an exploratory endpoint the biomarker analysis, which we will conduct in the CTCs we isolate. We were happy to have access to novel technology that can detect many more CTCs than EpCAM-dependent technology,&rdquo; Perez said.

Perez and her team have already analyzed samples from 80% of patients. The researchers looked at the number of CTCs, the percentage of cells staining positive for a given biomarker, and mean fluorescence intensity of the biomarker. &ldquo;We tested for markers that may be correlated with the activity of topoisomerase 1 inhibitors,&rdquo; she said. These biomarkers include Top1, Top2, Rad51, &gamma;H2Ax, Ki67, and ABCG2.

In San Antonio, the researchers described the initial CTC collection. &ldquo;We made two observations,&rdquo; Perez stated. &ldquo;We can detect CTCs in 97% of samples at baseline, and we get high-yield CTCs that allow us to do molecular profiling.&rdquo;

This reflects a much lower technical failure rate than occurs with older methods, where about 50% of patients yield CTCs, she said. With ApoStream&reg;, the mean number of CTCs was 472 per 7.5-mL sample.

Perez added that the CTCs are &ldquo;viable,&rdquo; allowing the researchers to conduct a variety of translational studies on them.

Perez E, Caygill K, Hannah AL, et al. Etirinotecan pegol target-specific pharmacodynamic biomarkers in circulating tumor cells from patients with metastatic breast cancer in the phase 3 BEACON study. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13

Awada A, Garcia AA, Chan S, et al, for the NKRT-102 Study Group. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study.

An international team of investigators is evaluating the novel topoisomerase-1 inhibitor etirinotecan pegol in patients with metastatic breast cancer, and at the same time evaluating target-specific biomarkers in CTCs.

Biomarker-Driven Trial of Novel Topo-1 Inhibitor Debuted

A potential pathogenic role for the androgen receptor (AR) exists for some breast cancer (BC) subtypes according to 2 new studies presented at the San Antonio Breast Cancer Symposium (SABCS) 2014.

Research from the University of Colorado Cancer Center in Denver showed that preventing AR nuclear localization slows tumor growth in estrogen receptor positive (ER+) BC and also demonstrated that certain triple-negative breast cancer (TNBC) subtypes depend on AR activity. In addition, the researchers showed that simultaneous inhibition of AR and the HER2/PI3K/mTOR pathway may be more effective than inhibition of the HER2/PI3K/mTOR pathway alone.

The AR is involved in prostate cancer, similar to the involvement of the estrogen receptor (ER) in breast cancer. However, about 75% of breast cancers express AR, and the expression varies by subtype, appearing in approximately 88% of ER+ BC, 50% of HER2+ BC, and 20% of TNBC.

In postmenopausal women, the level of circulating androgens is greater than estrogen, and the AR is more widely expressed in BC than estrogen or progesterone receptors.

Jennifer Richer, PhD, head of the research team that produced the studies commented that a major revolution may be about to occur for the treatment of breast cancer. &ldquo;We've known for years that prostate cancer is driven by androgens, and now it's increasingly clear that androgens and androgen receptors can influence many breast cancers as well,&rdquo;

Richer noted in a written release from the University of Colorado. &ldquo;Targeting androgen receptors in breast cancer gives us a new way to attack the disease," she added.

With no targeted therapies currently available, TNBC has a poor prognosis despite initial responses to conventional chemotherapy. Reports have shown that up to one-third of TNBCs express AR, and research presented at SABCS showed that in AR+ TNBC, inhibiting AR activity with the antagonist enzalutamide (ENZ) prevented AR nuclear localization in response to ligand binding (dihydrotestosterone), reduced proliferation in 2D culture, and decreased anchorage-independent growth.

In addition to reduced proliferation, treatment with ENZ altered cellular morphology and significantly decreased cancer cell migration and invasion. Microarray profiling suggested that AR influences cell proliferation, migration, and invasion through regulation of the EGFR ligand amphiregulin, a protein previously implicated in cancer progression

According to Valerie Barton, a graduate student in the Richer lab and lead author on the study, drugs such as ENZ block the action of androgen receptors and decrease the production of amphiregulin, thereby killing TNBC cells.

AR activation affects several cellular functions and signalling networks, including the HER2/PI3K/mTOR pathway. Inhibitors of the pathway (anti-HER2 trastuzumab [TRAS] and anti-mTOR everolimus [EVE]) have shown clinical benefit, and another line of inquiry from the Richer lab sought to determine whether AR inhibition (using ENZ) would enhance the efficacy of these agents.

HER2+ and TNBC cell lines were treated with ENZ, TRAS, and EVE alone or in combination. The combination of ENZ with TRAS or EVE inhibited cell proliferation more effectively than either drug alone. The researchers, led by Michael Gordon, PhD, concluded that through a distinct mechanism, AR inhibition acts synergistically with inhibitors of the HER2/PI3K/mTOR pathway to decrease proliferation and that &ldquo;combination therapies containing ENZ may provide benefit for multiple BC subtypes, including HER2+ and triple negative BC.&rdquo;

For tumors expressing ER+, controversy exists over the role of AR. In the absence of estradiol (E2), activated AR increases growth of ER+ breast cancer cells, and AR inhibition by bicalutamide (Bic) or ENZ blocks this proliferation. However, ENZ, but not Bic, also inhibits E2-mediated proliferation of ER+ BC cells. Because ENZ blocks nuclear localization of ligand-bound AR, the current study evaluated whether AR nuclear localization is necessary for E2-mediated proliferation in ER+/AR+ BC. Results showed that ENZ inhibited E2-induced proliferation. The agent worked synergistically with ER antagonists, tamoxifen and fulvestrant. E2-induced expression of ER target genes was inhibited by ENZ but not by Bic.

Treatment with dihydrotestosterone (DHT) or E2 induced translocation of AR to the nucleus. The E2-induced translocation only occurred in ER+ cells, further suggesting a role for AR in E2-induced ER activity. ENZ inhibited AR nuclear translocation, and in vivo, ENZ inhibited E2-induced tumor growth as effectively as tamoxifen. The combination of tamoxifen and ENZ was more effective than either agent alone.

Nicholas D&rsquo;Amato, lead author on the study and a postdoctoral researcher in the Richer lab, explained that tamoxifen and other drugs that target ER+ breast cancer are effective, but resistance and recurrence are still big problems.

Up to half of ER+ tumors are resistant to endocrine therapies, and all metastatic ER+ BCs acquire resistance. AR overexpression induces tamoxifen resistance, and previous research from the group showed that the ratio of AR to ER influences the response to therapy. The research presented at the conference showed that the nuclear localization of AR decreases ER activity and tumor growth in ER+/AR+ cancers, and inhibition by ENZ may be effective, particularly in combination with antiestrogen therapies, because it effects ER through an indirect mechanism.

According to 2 new studies presented at SABCS 2014, a potential pathogenic role for the androgen receptor (AR) exists for some breast cancer (BC) subtypes.

In AR+ TNBC, inhibiting AR activity with the antagonist enzalutamide prevented AR nuclear localization in response to ligand binding (dihydrotestosterone), reduced proliferation in 2D culture, and decreased anchorage-independent growth. It also altered cellular morphology and significantly decreased cancer cell migration and invasion.

Researchers treated HER2+ and TNBC cell lines with enzalutamide, trastuzumab, and everolimus alone or in combination and demonstrated that the combination of enzalutamide with trastuzumab or everolimus inhibited cell proliferation more effectively than either drug alone

Results of one study showed that enzalutamide inhibited estradiol-induced proliferation and that it worked synergistically with ER antagonists, tamoxifen and fulvestrant.

The 3 studies from the Richer lab point to a pathogenic role for AR in some breast cancers, and AR inhibition by ENZ demonstrates its potential as a therapeutic target in certain BC subtypes. &ldquo;Women with breast cancer do not routinely receive testing for the androgen receptor,&rdquo; Richer noted.

&ldquo;If the androgen receptor is outside the nucleus, both estrogen and androgen-driven tumor growth is inhibited,&rdquo; noted Richer in a written release. &ldquo;Our research suggests that the androgen receptor may serve as a therapeutic target in both estrogen receptor-positive and negative breast cancers.&rdquo;

Collins LC, Cole KS, Marotti JD, et al. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study. Mod Pathol. 2011;24:924-931.

Three San Antonio studies target androgen in breast cancer [news release]. Denver, CO: December 11, 2014. http://www.eurekalert.org/pub_releases/2014-12/uocd-3sa121014.php. Accessed December 16, 2014.

Barton VN, D&rsquo;Amato NC, Gordon MA, et al. Multiple subtypes of triple negative breast cancer are dependent on androgen receptor. Presented at: San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract P3-04-02.

Gordon MA, D&rsquo;Amato N, Gu H, et al. Targeting multiple pathways in breast cancer: androgen receptor, HER2, and mTOR. Presented at: San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract P6-03-07.

D&rsquo;Amato NC, Jacobsen BM, Cochrane DR, et al. Inhibiting androgen receptor nuclear localization decreases estrogen receptor (ER) activity and tumor growth in ER+ breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract P3-04-06.

Anti-Androgen Not for Male Cancers Alone

An ongoing clinical trial will determine whether the addition of weekly nab-paclitaxel to gemcitabine or carboplatin improves progression-free survival (PFS) versus the gemcitabine-carboplatin doublet as first-line therapy for patients with triple-negative metastatic breast cancer (TNMBC).

Still in the patient-accrual stage, the phase II/III trial will involve a cumulative total of almost 800 patients with untreated TNMBC,

, a medical oncologist at Sarah Cannon Research Institute in Nashville, Tennessee, and colleagues reported in a poster presentation at the San Antonio Breast Cancer Symposium (SABCS) 2014.

During the phase II portion of the study, investigators will enroll 240 patients, who will be randomized to nab-paclitaxel 125 mg/m

or carboplatin AUC 2 or to the gemcitabine-carboplatin doublet. The primary objectives are to evaluate the safety and efficacy of the nab-paclitaxel regimens and to identify the nab-paclitaxel doublet to carry forward into the phase III trial. The primary endpoint of phase II is investigator-assessed PFS.

The phase III investigation will compare the nab-paclitaxel regimen chosen from phase II with the gemcitabine-carboplatin doublet in 550 patients. The primary endpoint is PFS as assessed by independent radiology review.

Eligible patients have pathologically confirmed triple-negative breast cancer at screening and measurable disease and estrogen and progesterone receptor expression <1%, and are HER2 negative as defined by immunohistochemistry (IHC) 0 or +1, fluorescent in situ hybridization (FISH) negative, or IHC+2 and FISH negative. Patients must have received adjuvant or neoadjuvant anthracycline therapy (unless ruled out by treating physician) or an alternative adjuvant/neoadjuvant regimen, but they must not have undergone prior therapy for metastatic disease.

&ldquo;Biomarker analyses may advance the current understanding of triple-negative breast cancer biology and response to treatment,&rdquo; Yardley and colleagues noted in their SABCS poster presentation. &ldquo;This study may identify a nab-paclitaxelbased cytotoxic chemotherapy combination as a new first-line standard treatment regimen for triple negative metastatic breast cancer.&rdquo;

According to a representative for study sponsor Celgene, the phase II component of the trial should be completed during 2015 in time for reporting by the end of the year.

An ongoing clinical trial will determine whether the addition of weekly nab-paclitaxel to gemcitabine or carboplatin improves PFS versus the gemcitabine-carboplatin doublet as first-line therapy for patients with metastatic TNBC.

Trials Seek Optimal nab-Paclitaxel Regimen for First-Line Use in TNMBC

Beth Overmoyer, MD, director, Inflammatory Breast Cancer Program, Dana-Farber Cancer Institute, discusses obesity as a risk factor for inflammatory breast cancer.

Obesity as a Risk Factor for Inflammatory Breast Cancer

William J. Gradishar, MD, Betsy Bramsen Professorship of Breast Oncology, Professor in Medicine-Hematology/Oncology, Northwestern University Feinberg School of Medicine, discusses advances in the last year in the treatment of patients with HER2-positive breast cancer.

William J. Gradishar, MD, discusses advances in the last year in the treatment of patients with HER2-positive breast cancer.

Advances in the Treatment of HER2-Positive Breast Cancer

Edith A. Perez, MD, the deputy director at large for the Mayo Clinic Cancer Center, comments on immune checkpoint inhibition for the treatment of breast cancer.