Adjuvant AROMASIN® Most Beneficial for Premenopausal Women with High Risk Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues. Presently available therapies include Tamoxifen and other Selective Estrogen Receptor (ER) Modulators, which modulate ER alpha activity, Aromatase Inhibitors (AIs) and Ovarian ablation that decrease estrogen production and FASLODEX® (Fulvestrant) that down regulates Estrogen Receptor. Aromatase Inhibitors are often prescribed due to their superiority over Tamoxifen, for postmenopausal women with Hormone Receptor positive breast tumors, in adjuvant as well as metastatic settings. Aromatase Inhibitors by themselves however, are not effective in premenopausal women, as these individuals derive their estrogen mainly from ovaries and not extragonadal tissue.

The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) are two phase III randomized trials, conducted at the same time and included premenopausal women (average age was 43 years) with hormone receptor positive, early breast cancer. In the joint analysis of these two trials which included 4,891 women, the authors set out to answer 2 important questions – whether adjuvant AI treatment improves outcomes in this patient group, when their Ovarian Function is suppressed and whether there is any benefit with Ovarian Function suppression in premenopausal women suitable for adjuvant Tamoxifen. TEXT randomized patients within 3 months of surgery to 5 years of AROMASIN® (Exemestane) plus Ovarian Function Suppression (OFS) or 5 years of Tamoxifen plus OFS. The SOFT study randomized patients to 5 years of AROMASIN® plus OFS or 5 years of Tamoxifen plus OFS or 5 years of Tamoxifen alone. OFS choices included oophorectomy, ovarian irradiation or 5 years of TRELSTAR® (Triptorelin), a GnRH (Gonadotropin Releasing Hormone) agonist. The 5 year Disease Free Survival was 91.1% in the AROMASIN® plus OFS group and 87.3% in the Tamoxifen plus OFS group (HR=0.72, P<0.0002). Compared to patients receiving Tamoxifen plus OFS, AROMASIN® plus OFS reduced the relative risk of premenopausal women developing a subsequent invasive breast cancer by 28% and the relative risk of breast cancer recurrence by 34%.

The authors in this analysis examined the absolute treatment effect in the TEXT and SOFT trials across a continuum of recurrence risk, to help individualize decision making for endocrine therapy, in premenopausal women with Human Epidermal growth factor Receptor 2 (HER2) -negative disease. Incorporating age, nodal status, tumor size, grade, Ki-67 expression levels and hormone receptor status, a composite recurrence risk for each patient was determined, from a Cox model.

It was noted that patients in the SOFT trial who remained premenopausal after chemotherapy experienced absolute improvement of 5% or more in 5-year Breast Cancer-Free Interval with AROMASIN® plus OFS compared with Tamoxifen plus OFS or Tamoxifen alone, and this benefit was even higher, reaching 10% to 15% for the intermediate to high composite recurrence risk group of patients. Patients in the SOFT trial whose composite recurrence risk was low did not receive chemotherapy and did well with all endocrine therapies. For patients in the TEXT trial, the benefit of AROMASIN® plus OFS compared with Tamoxifen plus OFS was similar to the SOFT trial, with the 5-year Breast Cancer-Free Interval ranging from 5-15%. Again, patients not receiving chemotherapy and with lowest composite recurrence risk did well with both endocrine therapies.

The authors concluded that premenopausal women with hormone receptor-positive, HER2-negative disease, with high risk for recurrence based on clinicopathologic features, may experience a 10% to 15% improvement in the 5-year Breast Cancer-Free Interval with AROMASIN® plus OFS compared with Tamoxifen alone. Absolute Benefit of Adjuvant Endocrine Therapies for Premenopausal Women with Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Early Breast Cancer: TEXT and SOFT Trials.Regan MM, Francis PA, Pagani O, et al. Published online before print April 4, 2016, doi: 10.1200/JCO.2015.64.3171 JCO April 4, 2016 JCO643171

Five Year Follow up Data without Adjuvant Chemotherapy, Utilizing Oncotype DX 21-gene Recurrence Score Assay

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for early stage, hormone receptor positive, HER negative breast cancer patients, are often made based on tumor size, grade, immunohistochemical markers such as Ki-67, nodal status and 21-gene Recurrence Score (RS) assay.

The West German Study Group (WSG) PlanB phase III trial, used Recurrence Score assay prospectively, to define a low risk subset of patients with node negative disease with high risk traditional parameters and patients with node positive disease (HR+, HER2 negative), who could be treated with adjuvant endocrine therapy alone, sparing chemotherapy. In this study, patients with a Recurrence Score of 11 or less were defined as having low risk for recurrence, even in those considered to have tumor with high risk features such as large tumor size, high tumor grade and lymph node involvement. Patients were considered to be at intermediate or high risk if they had a Recurrence Score of 12 or more and 25 or more, respectively. Gluz and colleagues had previously reported 3-year follow up results of a planned interim analysis of this study, and were able to show significant difference between tumor grade, Ki-67 and Oncotype DX Recurrence Score.

In this current analysis, the authors reported the 5-year Disease Free Survival (DFS) outcomes of this large prospective trial. This analysis included data from 3,198 patients with early stage hormone receptor positive or HER2 negative breast cancer. The median age was 56 years and 32.5% of the patients had grade 3 tumors and 41% of the patients had node positive disease. Patients with a Recurrence Score of 11 or less received hormonal therapy and adjuvant chemotherapy was omitted. The intermediate and high risk patients were randomized to receive six cycles of TAXOTERE® (Docetaxel)/CYTOXAN® (Cyclophosphamide) or four cycles of ELLENCE® (Epirubicin)/CYTOXAN® followed by four cycles of TAXOTERE®. The primary endpoint was Disease Free Survival (DFS) defined as invasive or noninvasive relapse.

It was noted that the 5-year DFS in the low risk group was 94%, 84% in the high risk group and 94% in the intermediate risk group (P<0.001). It should be noted that approximately 15% of the patients in the clinically determined intermediate or high risk group, with 0-3 lymph node involvement, fell in the low genomic risk group (Recurrence Score of 11 or less) and received hormonal therapy alone.

The authors concluded that West German Study Group (WSG) PlanB study is the first trial that has reported five year survival data using 21-gene Recurrence Score assay, which can identify patients with early breast cancer, who would benefit from hormonal therapy alone and could be spared chemotherapy. Based on these data, 21-gene Recurrence Score has stronger prognostic value compared to immunohistochemical studies such as Ki-67 and hormone-receptor expression and should therefore be routinely incorporated in clinical practice as a decision making tool for this patient population, in addition tumor size, grade and nodal status. Prospective WSG Phase III PlanB trial: Clinical outcome at 5 year follow up and impact of 21 Gene Recurrence Score result, central/local-pathological review of grade, ER, PR and Ki67 in HR+/HER2- high risk node-negative and –positive breast cancer. Gluz O, Nitz U, Christgen M, et al. Abstract 8LBA. Presented at: 10th European Breast Cancer Conference; March 9-11, 2016; Amsterdam.

Impact of Treatment Delay on Clinical Outcomes in Breast Cancer Patients

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy and this is even more so true for HER positive and triple negative (ER, PR and HER negative) breast cancer patients, who are at an increased risk to develop recurrent disease. Even though majority of the patients start their adjuvant chemotherapy within 4-6 weeks following surgery, the impact of delay in the initiation of adjuvant therapy on outcomes, has remained unclear. Preclinical models have suggested that there is phase of increased angiogenesis and accelerated growth of micrometastases, as well as development of drug resistant clones, following removal of the primary tumor. Previously published data from a large meta-analysis had suggested that a four week delay in the initiation of adjuvant chemotherapy resulted in a 6% increase in the risk of death and an 8% increase in the risk of relapse. Nonetheless, over the past 2 decades, there has been increasing delay for both surgery and adjuvant chemotherapy treatment intervention, following diagnosis of breast cancer. These delays have been attributed to the increasing use of prognostic tools prior to treatment intervention, in order to optimize breast cancer care, germ-line genetic testing to plan appropriate surgical intervention, as well as patients seeking immediate reconstructive surgical options. Two studies addressed the impact of delay in treatment intervention following diagnosis of breast cancer, by investigating outcomes, in a very large group of patients with breast cancer.

In the study by Bleicher, et al., the relationship between the time from diagnosis to breast cancer surgery and survival was investigated, by collecting data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database and the National Cancer Database (NCDB). The SEER-Medicare cohort had 94,544 patients 66 years or older, diagnosed between 1992 and 2009 and the NCDB cohort included 115,790 patients 18 years or older, diagnosed between 2003 and 2005. Patients included in this analysis underwent surgery as initial treatment and had a diagnosis of non-inflammatory, non-metastatic, invasive breast cancer. The primary outcome was Overall and Disease-Specific Survival, as a function of time between diagnosis and surgery, measured in 30 day increments. They noted that with each interval of treatment delay increase, Overall Survival was lower (HR=1.09; P<0.001 in the SEER-Medicare cohort and HR=1.10; P<0.001 in the NCDB cohort). This relationship was statistically significant only in stages I and II breast cancer. The authors in this study concluded that longer time to surgery is associated with lower Overall and Disease-Specific Survival.

Chavez-MacGregor et al. analyzed the outcomes of 24, 843 patients in the California Cancer Registry with stage I-III invasive breast cancer, diagnosed between January 2005 and December 2010, and treated with adjuvant chemotherapy. Time to chemotherapy was defined as the number of days between surgery and the first dose of chemotherapy, and delayed treatment was defined as 91 or more days from surgery to the first dose of adjuvant chemotherapy. Median age at the time of diagnosis was 53 years, and median time to adjuvant chemotherapy was 46 days. Patients were evaluated for Overall Survival and Breast Cancer-Specific Survival. They noted that patients receiving adjuvant chemotherapy 91 or more days following surgery experienced worse Overall Survival (HR=1.34) and worse Breast Cancer-Specific Survival (HR=1.27) compared with patients receiving adjuvant chemotherapy within 31 days from surgery and these adverse outcomes were even more so, among patients with triple negative breast cancer (HR=1.53). Factors associated with adjuvant therapy delays included, low socioeconomic status, breast reconstruction, non-private insurance, and Hispanic or African American ethnicity. The authors in this study concluded that delaying initiation of adjuvant chemotherapy 91 days or more, results in adverse outcomes and this may be even more detrimental, in patients with triple negative breast cancer.

These two studies strongly suggest that treatment delays should be avoided in patients with early stage breast cancer and if surgery is to be delayed, neoadjuvant treatment approach may be reasonable, to avoid adverse outcomes.

Time to Surgery and Breast Cancer Survival in the United States. Bleicher RJ, Ruth K, Sigurdson ER, et al. JAMA Oncol. 2016;2:330-339.

Delayed Initiation of Adjuvant Chemotherapy Among Patients With Breast Cancer. Chavez-MacGregor M, Clarke CA, Lichtensztajn DY, et al. JAMA Oncol. 2016;2:322-329.

Aromatase Inhibitors-Induced Carpal Tunnel Syndrome

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their life time. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol, in extragonadal/peripheral tissues. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. The use of Aromatase Inhibitors (AIs) has been long associated with musculoskeletal symptoms, as well as accelerated bone loss, leading to a decrease in Bone Mineral Density (BMD). Approximately 25% of the patients on AIs are non-compliant during the first year of therapy and this has been attributed to musculoskeletal symptoms. Increased risk of Carpal Tunnel Syndrome (CTS) has also been reported with AIs.

Carpal tunnel syndrome (CTS), also called median nerve compression, is the most common entrapment neuropathy and results from compression of the median nerve, as it runs from the forearm into the palm of the hand, through the carpal tunnel. The carpal tunnel is a narrow and rigid passage at the base of the hand and houses the median nerve and tendons. In most cases, CTS is due to a congenital predisposition, with the carpal tunnel being simply smaller in some individuals than others. Secondary CTS is caused by any condition that further narrows this osteofibrous passage such as arthritis, acromegaly and mechanical problems in the wrist joint or effects the contents of this passage such as tenosynovitis, synovial hypertrophy, hypothyroidism, fluid retention during pregnancy or menopause, or the development of a cyst or tumor in the passage. Bilateral oophorectomy and use of the combined oral contraceptive have also been identified as risk factors for CTS. Patients often experience nocturnal paraesthesias in median nerve distribution (thumb, index and middle fingers), such as burning sensation, tingling, or heaviness, with the pain radiating to the forearm or elbow. It has been postulated that estrogen has antinociceptive properties and estrogen deprivation with AIs decreases the threshold for pain stimuli. Estrogen deprivation may also impact the metabolism of transverse carpal ligament on which estrogen and progesterone receptors are expressed and lack of estrogen may additionally result in morphological changes in the contents of carpal tunnel including, thickening of the tendon sheaths and fluid accumulation. This may directly induce CTS.

To address the risk factors and incidence of CTS in women taking AIs, the authors conducted an exploratory analysis of the International Breast Cancer Intervention Study II, a double-blind randomized clinical trial, in which women at increased risk of breast cancer were randomly assigned to receive ARIMIDEX® or placebo for 5 years. In this study, a total of 3,864 women were randomly assigned to receive either ARIMIDEX® (N=1920) or placebo (N=1944). The median age was 60 years and majority of the women (69%) had a BMI of greater than 25 kg/m2.

After a median follow up of 6.4 years, 96 patients had symptoms of Carpal Tunnel Syndrome (CTS). Patients receiving ARIMIDEX® were more likely to have CTS related symptoms than those receiving placebo (3.4% versus 1.6%; P<0.001). Eight of the 10 participants reported as having severe CTS were taking ARIMIDEX® (P =0.08). Eighteen women (0.9%) in the ARIMIDEX® group required surgical intervention for CTS compared to six women (0.3%) in the placebo group and this was significantly different (P=0.018). Participants experiencing CTS symptoms did so early in the course of treatment and only 6 women discontinued the allocated treatment. In addition to taking AIs, high Body Mass Index and prior complaints of musculoskeletal symptoms, were the only other risk factors for developing CTS.

The authors concluded that the use of ARIMIDEX® was associated with a higher incidence of Carpal Tunnel Syndrome (CTS), although few participants required surgery. Given the association between CTS and other musculoskeletal symptoms induced by AIs (Aromatase Inhibitors), the authors suggested that these findings induced by AIs, may share the same pathobiology. Anastrozole-Induced Carpal Tunnel Syndrome: Results from the International Breast Cancer Intervention Study II Prevention Trial. Spagnolo F, Sestak I, Howell A, et al. J Clin Oncol 2016;34:139-143

FDA Approves IBRANCE® in Combination with FASLODEX® for Advanced Breast Cancer

SUMMARY: The FDA on February 19, 2016, approved IBRANCE® (Palbociclib) in combination with FASLODEX® (Fulvestrant), for the treatment of women with Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative advanced or metastatic breast cancer, with disease progression following endocrine therapy. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and over 40,450 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole) and FEMARA® (Letrozole) are nonsteroidal Aromatase Inhibitors that binds reversibly to the aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Approximately 80% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6), phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. IBRANCE® (Palbociclib) is a reversible, oral, selective, small molecule inhibitor of Cyclin Dependent Kinases, CDK4 and CDK6, and prevents RB1 phosphorylation. IBRANCE® is the first CDK inhibitor approved by the FDA. It exhibits synergy when combined with endocrine therapies. In an open-label, randomized, phase II study, which included treatment naïve postmenopausal women with ER-positive, HER2-negative, advanced breast cancer, IBRANCE® given along with Aromatase Inhibitor FEMARA® (Letrozole), significantly prolonged Progression Free Survival, Overall Response rate and median duration of response, compared to FEMARA® alone. Based on this data, the U. S. Food and Drug Administration in February 2015, granted accelerated approval to IBRANCE® (Palbociclib), for use in combination with FEMARA®, in this patient population. FASLODEX® (Fulvestrant) is a selective estrogen receptor down-regulator presently indicated for the treatment of hormone receptor positive metastatic breast cancer patients, with disease progression following antiestrogen therapy.

The PALOMA3 is double-blind, phase 3 study in which the efficacy and safety of the combination of IBRANCE® and FASLODEX® was evaluated, in premenopausal or postmenopausal women, with hormone receptor positive, HER-2 negative, advanced breast cancer, who had disease progression during prior endocrine therapy. Five hundred and twenty one (N=521) patients were randomly assigned in a 2:1 ratio to receive either FASLODEX® 500 mg IM on days 1 and 15 during cycle 1, of a 28 day cycle, and then on day 1 of each cycle thereafter, along with IBRANCE® 125 mg PO daily for 3 weeks, followed by 1 week off (N=347) or FASLODEX® and placebo (N=174). ZOLADEX® (Goserelin) was administered to premenopausal or perimenopausal patients for the duration of study treatment, starting at least 4 weeks before randomization and continuing every 28 days. The median age was 57 years. One previous line of chemotherapy for metastatic disease was allowed and 79% were post-menopausal, 60% had visceral disease and 75% of the patients had received a previous chemotherapy regimen.

The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rates, safety and tolerability. At the time of the preplanned interim analysis, the median Progression Free Survival was 9.2 months in the FASLODEX® / IBRANCE® group and 3.8 months in the FASLODEX® /placebo group (HR=0.42; P<0.001). This PFS benefit was observed across all prespecified patient subgroups, regardless of menopausal status. The most common grade 3 or 4 adverse events in the FASLODEX® / IBRANCE® group were neutropenia (62.0%, vs. 0.6%) and fatigue (2.0% vs. 1.2%). The incidence of febrile neutropenia was very rare (0.6%) and similar in both treatment groups. Treatment discontinuation rate due to adverse events was 2.6% in the IBRANCE® group and 1.7% in the placebo group.

The authors concluded that IBRANCE® in combination with FASLODEX® more than doubled the Progression Free Survival in advanced breast cancer patients, with hormone receptor positive and HER-2 negative disease, who had progressed on prior endocrine therapy. This study has reinforced the importance of CDK4 and CDK6, as key targets for hormone receptor positive breast cancer. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. Turner NC, Ro J, Andre F, et al. N Engl J Med 2015; 373:209-219

Cardiac Outcomes of Patients Receiving Adjuvant Weekly TAXOL® and HERCEPTIN®

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their life time. Approximately, 246,660 new cases of invasive breast cancer were diagnosed in 2016 and 40,450 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 20-25% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. HERCEPTIN® binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). HERCEPTIN® in combination with chemotherapy has been proven to significantly improve Progression Free Survival and Overall Survival in patients with advanced breast cancer. Adjuvant chemotherapy in combination with HERCEPTIN® has been shown to reduce the relative risk of relapse by 52% and relative risk of death by 33%. The National Comprehensive Cancer Network (NCCN) has recommended adjuvant chemotherapy with HERCEPTIN® for patients with small, HER positive, node-negative tumors, including those with T1bN0 tumors, even though there are little or no data supporting this recommendation, because these patients are generally not included in adjuvant therapy studies. Further, the chemotherapy regimens often recommended (ACTH, TCH) along with HERCEPTIN® are relatively toxic.

In a previously published study, it was noted that a less toxic regimen such as HERCEPTIN®, given along with weekly TAXOL® (Paclitaxel), had significant efficacy in patients with node negative patients with tumors measuring up to 3 cm in greatest dimension, decreasing the risk of recurrence in this patient group, most notable during the first three years after diagnosis. (Tolaney SM, Barry WT, Dang CT, et al. N Engl J Med 2015;372:134-141). Risk risk factors associated with HERCEPTIN® induced cardiotoxicity include, age over 50 years, borderline LVEF (Left Ventricular Ejection Fraction) before HERCEPTIN® treatment, history of cardiovascular disease, cardiovascular risk factors such as diabetes, dislipidemia or elevated body mass index (>30), sequence in which chemotherapy is administered and prior treatment with Anthracyclines (cumulative doses more than 300 mg/m2). However, unlike Anthracycline induced cardiotoxicity, HERCEPTIN® induced cardiotoxicity is reversible and there are no ultrastructural changes noted in cardiomyocytes in HERCEPTIN® induced cardiotoxicity.

This publication is a secondary analysis of the above mentioned previously published study and the authors here reported the cardiac safety data of a HERCEPIN® based nonanthracycline treatment, (TAXOL® with HERCEPTIN®), for patients with early-stage, node negative, HER2 positive breast cancer and the utility of monitoring LVEF in this patient group. This clinical trial enrolled 406 patients with node-negative, HER2 positive breast cancer 3 cm, or smaller with a baseline LVEF of 50% or greater. Treatment consisted of TAXOL® 80 mg/m2 IV weekly administered concurrently with HERCEPTIN® IV for 12 weeks, followed by HERCEPTIN® monotherapy for 39 weeks. HERCEPTIN® could be administered 2 mg/kg weekly or 6 mg/kg every 3 weeks during the monotherapy phase. Radiation and hormone therapy were administered as planned, following completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Median age was 55 years and 29% of the patients had hypertension, and 7% had diabetes. The median follow up was 4 years.

It was noted that a significant, asymptomatic LVEF decline was seen in 3.2% of the patients and 0.5% developed grade 3 Left Ventricular Systolic Dysfunction. The median LVEF at baseline was 65%, at 12 weeks was 64%, at 6 months was 64%; and at 1 year was 64%. The authors concluded that cardiotoxicity from a combination of TAXOL® and HERCEPTIN® is low and a baseline LVEF assessment may be adequate for the majority of patients although serial LVEF assessments could be considered for patients considered at a higher risk for cardiotoxicity. Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer. Dang C, Guo H, Najita J, et al. JAMA Oncol. 2016;2:29-36

Use of Biomarkers to Guide Decisions on Systemic Therapy for Women with Metastatic Breast Cancer American Society of Clinical Oncology Clinical Practice Guideline

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. The American Society of Clinical Oncology (ASCO) guidelines on the use of tumor markers in breast cancer are meant to provide evidence-based recommendations and guidance to practicing oncologists, on the appropriate use of breast tumor biomarker assays, for management of patients with metastatic breast cancer. These recommendations are for women with metastatic breast cancer being considered for systemic therapy or for changes in the drug or regimen they are receiving.

These guidelines were compiled after reviewing 17 clinical publications following an extensive literature search between 2006 and 2014. They included 11 studies that reported discordance in expression of hormone receptors or HER-2 between primary tumors and metastases, one randomized controlled study that addressed the use of a biomarker to decide whether to continue or change a treatment regimen and 5 prospective and retrospective studies that evaluated the clinical utility of biomarkers.

Should metastases be biopsied or otherwise sampled to test for changes from the primary tumor with respect to ER, PR, or HER2 status?

Patients with accessible, newly diagnosed metastases from primary breast cancer should be offered biopsy for confirmation of disease process and testing of ER, PR, and HER2 status. They should also be informed that if discordances are found, evidence is lacking to determine whether outcomes are better with treatment regimens based on receptor status in the metastases or the primary tumor. With discordance of results between primary and metastatic tissues, the Panel consensus is to preferentially use the ER, PR, and HER2 status from the metastasis to direct therapy, if supported by the clinical scenario and the patient's goals for care.

For women with metastatic breast cancer and with known ER, PR, and HER2 status, which additional tumor markers have demonstrated clinical utility to initiate systemic therapy or direct selection of a new systemic therapy regimen?

Decisions on initiating systemic therapy for metastatic breast cancer should be based on clinical evaluation, judgment, and patient preferences. There is no evidence at this time that initiating therapy solely on the basis of biomarker results beyond those of ER, PR, and HER2 improves health outcomes.

For women with metastatic breast cancer and with known ER, PR, and HER2 status, which additional tumor markers have demonstrated clinical utility to guide decisions on switching to a different drug or regimen or discontinuing treatment?

Recommendations for tissue biomarkers: In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient's goals for care. There is no evidence at this time that changing therapy based solely on biomarker results beyond ER, PR, and HER2 improves health outcomes, quality of life, or cost effectiveness.

Recommendations for circulating tumor markers: In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient's goals for care. There is no evidence at this time that changing therapy based solely on circulating biomarker results improves health outcomes, quality of life, or cost effectiveness. CEA, CA 15-3, and CA 27-29 may be used as adjunctive assessments to contribute to decisions regarding therapy for metastatic breast cancer. Data are insufficient to recommend use of CEA, CA 15-3, and CA 27-29 alone for monitoring response to treatment. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments.

For biomarkers shown to have clinical utility to guide decisions on systemic therapy for metastatic disease in questions 2 and 3, what are the appropriate assays, timing, and frequency of measurement?

Decisions for systemic therapy should be influenced by ER, PR, and HER2. ASCO recently updated the guideline addressing optimization of HER2 assays. To date, clinical utility has not been demonstrated for any additional biomarkers.

Poznak CV, Somerfield MR, Bast RC, et al. J Clin Oncol 2015;33:2695-2704

Adjuvant PROLIA® Significantly Reduces Fracture Risk for Breast Cancer Patients on Aromatase Inhibitors

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues. Tamoxifen is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. Anastrozole,Letrozole and Exemestane are Aromatase Inhibitors that bind reversibly to the aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Aromatase inhibitors are associated with accelerated bone loss, leading to a decrease in Bone Mineral Density (BMD) and can thus cause osteopenia and osteoporosis, thereby increasing fracture risk. According to the WHO definitions, a healthy 30 year old adult (young adult) with the ideal Bone Mineral Density (BMD) is given a T-score of 0. A normal BMD is within 1 Standard Deviation-SD (+1 or −1) of the young adult mean. Osteopenia is between 1 and 2.5 SD below the young adult mean (−1 to −2.5 SD). Osteoporosis is 2.5 SD or more below the young adult mean (−2.5 SD or lower).

PROLIA® (Denosumab) is a monoclonal antibody that inhibits osteoclast formation, function and survival by selectively targeting the RANK ligand. In this randomized, double-blind, phase III trial, the authors evaluated the benefits of the anti-RANK ligand antibody PROLIA® (Denosumab) on bone health, in postmenopausal patients, with early stage hormone receptor-positive breast cancer, treated with Aromatase Inhibitors. Of the 3425 enrolled patients, 3420 patients were randomly assigned to receive PROLIA® 60 mg (N=1711) or placebo (N=1709) subcutaneously every 6 months. Majority of the patients participating in this study had breast cancer with good prognosis and only 25% of the patients required adjuvant chemotherapy. Patient received a median of 7 doses of PROLIA® . The primary endpoint was time from randomization to first clinical fracture.

Compared with placebo, PROLIA® significantly delayed time to first clinical fracture (HR=0.50; P<0•0001), with the PROLIA® group, half as likely to have a first clinical fracture as the placebo group. This benefit of lowering fracture risk was seen in subgroups of patients with BMD T-score of less than –1 as well as those with BMD T-score of -1 or greater. Further, patients in the PROLIA® group had improvements in BMD from baseline, of the lumbar spine, total hip, and femoral neck, compared to the placebo group, which showed worsening at all sites (P<0.0001). At 3 years, patients in the PROLIA® group had significantly lower risk of both new, or worsening vertebral fractures. No cases of osteonecrosis of the jaw bone were reported.

The authors concluded that PROLIA® administered in an adjuvant setting, significantly reduces the risk of fractures in postmenopausal women with breast cancer receiving Aromatase Inhibitors, without added toxicity. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Gnant M, Pfeiler G, Dubsky PC, et al. The Lancet 2015;386:433-443

FDA Approves DigniCap Cooling System for Prevention of Chemotherapy Induced Alopecia

SUMMARY: The FDA on December 8, 2015 allowed the marketing of the first cooling cap in the US, Dignitana DigniCap Cooling System, to reduce hair loss, in female breast cancer patients undergoing chemotherapy. Alopecia (hair loss) is a common side effect of several chemotherapeutic agents and can be emotionally traumatic. Even though temporary, minimizing or alleviating hair loss, can have a significant impact on patients psychological well being and willingness to pursue necessary treatment. Presently available non-FDA approved cooling devices include Penguin Cold Caps and Paxman Scalp Cooling System, although the later is not available in the US. One of the major concerns with cold caps use has been the risk for scalp metastasis due to decreased chemotherapy access to the scalp tissue from vasoconstriction associated with cooling devices. It is clear now that that the risk of metastases to the scalp is extremely rare and low (1.2%) and even lower as an initial event for advanced disease.

The Dignitana DigniCap computer-controlled cooling system pumps liquid coolant through a head-worn silicone cooling cap during chemotherapy treatment. This cooling cap is covered by an outer insulating cap which holds the cooling cap in place. The circulating coolant inside the cap gradually gets colder. The cold and near freezing temperature constricts the blood vessels in the scalp, which, in turn reduces chemotherapy access in the hair follicles, as well as metabolic activity of the hair follicle cells, thus slowing cell division. This combined action impairs the effect of chemotherapy on hair follicles and reduces chemotherapy induced hair loss.

The FDA approval was based on a multicenter prospective open-label, nonrandomized study in which the efficacy of the cooling system was studied in 122 women with Stage I and Stage II breast cancer who were receiving chemotherapy regimens associated with hair loss. The primary endpoint was patient self-assessment of hair loss using standardized photographs at three to six weeks after the last chemotherapy cycle. A score of 0-2 (50% or less hair loss) was defined as treatment success. Patients who chose not to undergo scalp cooling were enrolled in a control group. It was noted that more than 66 percent of patients treated with the DigniCap reported losing less than half their hair whereas 94% had more than 75% hair loss in the control group. The most common side effects with the scalp cooling system included cold-induced headaches and neck and shoulder discomfort, chills and pain associated with wearing the cooling cap for prolonged period of time.

The authors concluded that the DigniCap System is highly effective in reducing chemotherapy-induced alopecia and the FDA approval of this scientifically proven option will provide a major relief for cancer patients receiving chemotherapy. Clinical performance of the DigniCap system, a scalp hypothermia system, in preventing chemotherapy-induced alopecia. Rugo HS, Klein P, Melin SA, et al. J Clin Oncol 33, 2015 (suppl; abstr 9518)

Preserving Fertility with ZOLADEX® in Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues. Premature Ovarian Failure (POF) is a common unintended consequence of chemotherapy in premenopausal women. Besides of loss of fertility, which can influence treatment decisions in young women, ovarian failure can lead to menopausal symptoms, sexual dysfunction and loss of bone density.

POEMS (Prevention of Early Menopause Study) is a randomized phase III trial designed to evaluate whether the addition of LHRH (Luteinizing Hormone-Releasing Hormone) analog Goserelin (ZOLADEX®), which suppresses the production of estrogens, to Cyclophosphamide based chemotherapy, would reduce POF in breast cancer patients, when compared to chemotherapy alone. Premenopausal patients less than 50 years of age, with hormone receptor negative (ER/PR negative ), Stage I-IIIA breast cancer, scheduled to receive chemotherapy, were randomly assigned to receive standard Cyclophosphamide based chemotherapy with or without monthly ZOLADEX® . Patients in the ZOLADEX® group received 3.6 mg SQ starting 1 week prior to the first dose of chemotherapy.

The primary endpoint was ovarian failure at two years (defined as amenorrhea for the prior 6 months AND post-menopausal FSH level). Other endpoints included pregnancy and survival rates. The median age of the patients was 38 years and median follow up was 4.1 years. Of the 218 evaluable patients, 135 premenopausal women were evaluable for the primary end point. POF rates were 22% in the chemotherapy alone group and 8% in the ZOLADEX® group (P=0.04). When the definition of POF was more liberal to include EITHER amenorrhea or elevated FSH but not both, POF rates were 45% in the chemotherapy alone group and 20% in the ZOLADEX® group (P=0.006). Among the 218 evaluable patients, more women in the ZOLADEX® group achieved at least one pregnancy (21%) compared to 11% in the chemotherapy alone group (P=0.03). Secondary outcomes also favored the ZOLADEX® group with a Disease free Survival (DFS) rate of 78% in the chemotherapy alone group compared with 89% in the ZOLADEX® group (P=0.04) and Overall Survival (OS) rate of 82% in the chemotherapy alone group compared with 92% in the ZOLADEX® group (P=0.05).

The authors concluded that the addition of ZOLADEX® to chemotherapy improved fertility prospects with a lower incidence of Premature Ovarian Failure and more pregnancies. Further, the improved Disease Free Survival and Overall Survival are important additional perks and prevention of Premature Ovarian Failure with ZOLADEX® may be a consideration not only in premenopausal breast cancer patients but also in other malignancies such as lymphomas, when treated with similar chemotherapeutic agents. Goserelin for Ovarian Protection during Adjuvant Chemotherapy for Breast Cancer. Moore HC, Unger JM, Phillips K, et al. N Engl J Med 2015; 372:923-932