Tag: 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, 233,000 new cases of invasive breast cancer will be diagnosed in 2014 and 40,000 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive and 15%-20% of breast cancers overexpress HER2/neu oncogene. As such a significant number of breast cancers are Hormone Receptor (HR) positive and HER2 negative. Aromatase Inhibitors (AI’s) are often prescribed, due to their superiority over Tamoxifen, for post menopausal women with HR+ and HER2-negative breast tumors, both in adjuvant as well as metastatic settings. These patients will eventually develop progressive disease on endocrine therapy with AI’s, attributed to endocrine resistance. The average Progression Free Survival for these patients is 4-6 months when treated with other hormonal interventions including higher doses of FASLODEX® (Fulvestrant). Further, FASLODEX® has not been shown to be superior to steroidal or non steroidal AI’s. The mechanism of endocrine resistance has been attributed to cross talk between Estrogen Receptor signaling and PI3K/AKT/mTOR pathway. The PI3K/AKT/mTOR is a complex pathway, essential for cell proliferation, survival and apoptosis (programmed cell death). This pathway is of interest because of its increased activity in malignant cells as a result of amplification or mutation of the genes associated with PI3-kinase (phosphatidylinositol-3 kinase) and AKT, as well as loss of function of PTEN. PTEN normally prevents activation of AKT and its downstream pathways. Therefore, elevated ER signaling and breast cancer progression has been associated with activation of this mTOR (mammalian Target Of Rapamycin) pathway. Everolimus (AFINITOR®) is a mTOR inhibitor that has been shown to inhibit ER signaling and restore sensitivity to anti-estrogen therapies. With this preclinical knowledge, the Breast cancer trial of OraL EveROlimus-2 (BOLERO-2), which is a randomized, multicenter phase III trial was conducted to evaluate the benefit of combining steroidal AI, AROMASIN® (Exemestane) and an mTOR inhibitor AFINITOR®, for treatment of postmenopausal patients with HR+ and HER2 negative advanced breast cancer, who had either recurrent or progressive disease after non steroidal AI’s. Seven hundred and twenty four (N=724) patients were randomly assigned in a 2:1 ratio to receive either a combination of a steroidal AI, AROMASIN® at 25 mg PO QD and AFINITOR® at 10 mg PO QD (N=485) or AROMASIN® along with a placebo (N=239). Both treatment groups were well balanced and patients were stratified according to sensitivity to previous hormonal therapy and presence of visceral metastases. The primary endpoint for this study was Progression Free Survival (PFS) and secondary endpoints included overall Response Rate (RR), Clinical Benefit Rate (CBR defined as complete response + partial response + stable disease for at least 6 months), Overall Survival, Quality of Life, changes in bone marker levels and patient safety. In this study, close to 60% of the patients had visceral disease and approximately 80% of the patients had prior therapies for metastatic disease, with only 20% receiving the study drugs as their first therapy for metastatic disease. The combination of AFINITOR® and AROMASIN® significantly prolonged PFS compared to AROMASIN® alone (11 vs 4.1 months, HR=0.38, P<0.0001) and the Clinical Benefit Rate was 51% in the combination group and 26% in the AROMASIN® alone group (P<0.0001). The combination of AFINITOR® and AROMASIN® benefitted all subgroups of patients including those who had disease recurrence during or after neoadjuvant/adjuvant non steroidal AI therapy, those with visceral and bone metastases, as well as those who had prior chemotherapy. The most common adverse events in all age groups were rash, stomatitis, fatigue, diarrhea and nausea and these toxicities were manageable. The authors concluded that AFINITOR® given along with AROMASIN® in the study population can decrease the risk of disease progression by 60% and can double the Clinical Benefit Rate, compared to AROMASIN® alone, even in patients 65 years of age or older, thereby delaying the need for chemotherapy. Beck JT, Hortobagyi GN, Campone M, et al. Breast Cancer Res Treat. 2014; 143: 459–467

It appears that Yoga can substantially reduce Inflammation, Fatigue and improve Vitality in breast cancer survivors. This was substantiated in a randomized trial, which enrolled breast cancer patients following local intervention and adjuvant chemotherapy. The authors were also able to measure and demonstrate a drop in the cytokines associated with inflammation, such as Interleukin-6 (IL-6), Interleukin-1beta (IL-1b) and Tumor Necrosis Factor-alfa (TNFa), with Yoga intervention. These interesting and intriguing findings were published in the Journal of Clinical Oncology. A summary of this study is available to review at www.oncoprescribe.com.

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, 233,000 new cases of invasive breast cancer will be diagnosed in 2014 and 40,000 women will die of the disease. According to the SEER database, the 5 year survival of women with early stage breast cancer is well over 90%. This is mainly because of early detection and effective therapies. A third of these cancer survivors however are likely to be physically inactive due to fatigue, general deconditioning and effects of cancer treatment. There is a reduction in their cardiorespiratory fitness. Chronic inflammation has been implicated in decreased physical functioning, disability and mortality, even in those who are in remission. Regular exercise has been shown to reduce inflammation and fatigue. The authors in this study evaluated the impact of Yoga, which provides graded exercise, on inflammation, mood and fatigue. Yoga by definition is a physical, mental, and spiritual practice and hatha Yoga which is practiced in the Western countries, consists of physical and mental strength building exercises and postures. In this randomized controlled study, 200 breast cancer survivors between ages 27 and 76 years, were assigned to either the Yoga group (N=100) or control/no Yoga group (N=100). Both groups were well balanced with no significant difference between the groups in measures of activity, fatigue, body mass index or depressive symptoms. Enrolled patients were stratified by cancer stage and whether radiation therapy was given or not. Participants had Stage 0 – Stage IIIa breast cancer and had completed cancer treatment within the past three years and were at least 2 months post surgery, adjuvant chemotherapy or radiation treatment. Patients in the Yoga group participated in a 90 minute Yoga class, twice a week for 12 weeks (3 months). The protocol included the measurement of cytokines associated with inflammation and they included Interleukin-6 (IL-6), Interleukin-1beta (IL-1b) and Tumor Necrosis Factor-alfa (TNFa). In addition, other validated instruments were utilized to measure Fatigue and Vitality. Immediately following 12 weeks of Yoga intervention, there was a significant improvement in the Vitality score in the Yoga group (P=0.01) and at 3 months post intervention, the Vitality score was even higher (P=0.01). Fatigue was significantly lower 3 months post intervention, in the Yoga group (P=0.002). At 3 months post intervention, all inflammatory cytokines were lower as well, in the Yoga group – IL-6 (P=0.027), TNFa (P=0.027) and IL-1b (P=0.037). More frequent Yoga practice resulted in greater benefits, with improved sleep and decreased inflammation. It should be noted that sleep problems are 2-3 times more common in cancer survivors and close to two thirds of the cancer survivors experience insomnia. The authors concluded that this is the first and largest randomized controlled study that has demonstrated that practice of Yoga or similar such activities, can substantially reduce inflammation and Fatigue and improve Vitality in breast cancer survivors. Kiecolt-Glaser JK, Bennett JM, Andridge R, et al. J Clin Oncol 2014;32:1040-1049

SUMMARY:It has been well recognized that patients with Breast Cancer with Isolated LocoRegional Recurrences (ILRR), without evidence of distant metastasis, are at a high risk of developing subsequent distant metastasis and may have poor outcomes, in spite of surgical resection of the ILRR. The role of systemic chemotherapy following surgery in this patient population has remained unclear although hormonal intervention in ER positive patients demonstrated disease free survival benefit. To address this question, three cooperative groups, The International Breast Cancer Study Group (IBCSG), Breast International Group (BIG) and NSABP collaborated and conducted this study to find out whether adjuvant chemotherapy improves the outcome of patients with ILRR following surgical resection. In this multicenter trial, 162 patients were randomly assigned to receive chemotherapy (N=85) or no chemotherapy (N=77). Eligible patients had histologically proven first ILRR resected and radiotherapy was recommended for all patients, but was mandated for those with microscopically involved surgical margins. All patients with ER or PR positive recurrent tumors received endocrine therapy and patients randomized to the chemotherapy group received at least two standard cytotoxic drugs (investigators choice) for 3-6 months. Both treatment groups were well balanced, and hormone receptor status was positive in 68% of the patients belonging to each group. The primary endpoint was Disease Free Survival and secondary endpoints included Overall Survival. The five year Disease Free Survival in the adjuvant chemotherapy group was 69% compared with 57% in the no chemotherapy group (HR=0.59, P=0.046). The five year overall survival was also significantly longer in the chemotherapy group compared to the no chemotherapy group (88% vs 76%, HR=0.41, P=0.024). With regards to the chemotherapy benefit based on hormone receptor status, patients with hormone receptor negative ILRR, had a longer Disease Free Survival with adjuvant chemotherapy (P=0.046). The authors concluded that adjuvant chemotherapy significantly improves Disease Free and Overall Survival in Breast Cancer patients with ILRR. This benefit is even more so, in those with ER negative ILRR. Adjuvant chemotherapy should therefore be considered in this patient population. Aebi S, Gelber S, Anderson SJ, et al. The Lancet Oncology 2014;15:156-163

SUMMARY: Breast cancer is the most common cancer among women in the United States and 1 in 8 women will develop invasive breast cancer during their lifetime. Screening mammography complemented by breast self exam and clinical breast exam has resulted in early detection of breast cancer and successful outcomes. Even though mammography is a sensitive screening test, a small percentage of breast cancers may not show up on mammograms but may be palpable on examination by the patient or the clinician. Further, mammograms are less likely to find breast tumors in younger women with dense breast tissue. A breast Magnetic Resonance Imaging (MRI) is more sensitive than mammography although the specificity of a breast MRI is lower, resulting in a higher rate of false-positive findings and potentially unnecessary biopsies. Microcalcifications in the breast can be missed by a breast MRI. Taking these factors into consideration, appropriate utilization of breast MRI becomes relevant. The American Cancer Society (ACS) recommends an annual MRI as an adjunct to screening mammogram and clinical breast exam in certain groups with increased risk of breast cancer (See Figures). The authors conducted this study to determine the utilization of breast (MRI) in community settings. In this retrospective study, the authors reviewed data on 10,518 women from a not-for-profit health plan, and these women had at least one breast MRI between January 2000 and December 2011. The appropriateness of a breast MRI was determined using a prediction model obtained from electronic medical records on a subset of patients. Between 2000 and 2009, there was a 20-fold increase in the use of breast MRI from 6.5 per 10,000 women in the year 2000 to 130.7 per 10,000 in 2009. This increase then declined and stabilized to 104.8 per 10,000 by 2011. With regards to indications for a breast MRI, 51.7% had a family history of breast cancer, 30.1% had a personal history of breast cancer and 3.5% of women had a documented genetic mutation. It is interesting to note that of those who received screening or surveillance breast MRI’s, only 21% fulfilled the American Cancer Society (ACS) criteria for a breast MRI. Conversely, fewer participants (48.4%), with documented deleterious genetic mutations, received breast MRI screening. The authors concluded that breast MRI was over utilized in those who did not fit the ACS criteria and was under utilized in those with documented genetic mutations. It is their opinion that routine breast MRI screening is not recommended for a new breast cancer diagnosis or for breast cancer surveillance and should only be considered for the group of individuals who have the most benefit. Breast MRI is performed preferably between days 7-15 of menstrual cycle for premenopausal women, using a dedicated breast coil, with the ability to perform a biopsy under MRI guidance by experienced radiologists, during the same visit. Stout NK, Nekhlyudov L, Li L, et al. JAMA Intern Med. 2014;174:114-121.

SUMMARY: The FDA on September 30, 2013 granted accelerated approval to PERJETA® (Pertuzumab) for use in combination with HERCEPTIN® (Trastuzumab) and other chemotherapy for the neoadjuvant (preoperative) treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or with positive lymph nodes), as part of a complete treatment regimen for early breast cancer. Following surgery, patients should continue to receive HERCEPTIN® to complete one year of treatment. The HER family of receptors consist of HER1, HER2, HER3 and HER4. These proteins are transmembrane tyrosine kinases and are involved in normal cell growth and differentiation. HER1 is also known as Epidermal Growth Factor Receptor or EGFR. These receptors are activated following ligand binding, receptor pairing or dimerization and phosphorylation. This dimerization (receptor pairing) occurs often within the HER family of receptors. This has been no ligand identified for HER2 receptor, although it is able to form homo and heterodimers with other members of the HER family readily. Dimerization of HER2 and HER3 is believed to produce the strongest mitogenic signaling and activates two important pathways that regulate cell survival and growth – Mitogen Activated Protein Kinase (MAPK) pathway and PhosphoInositide 3-Kinase (PI3K) pathway. For this reason inhibiting HER2 dimerization appears to be an important step in the treatment of cancer. Overexpression of HER2 in breast cancer has been associated with higher risk for relapse as well as overall survival. Approximately 20 percent of breast cancers are HER2-positive. HERCEPTIN® is a humanized monoclonal antibody targeting HER2. It binds to the extracellular subdomain IV of the receptor and disrupts ligand independent HER2 downstream cell signaling pathways. PERJETA® is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors, ie. HER3, HER1 and HER4. Thus HERCEPTIN® along with PERJETA® provide a more comprehensive blockade of HER2 driven signaling pathways. The accelerated approval of PERJETA® for the neoadjuvant treatment of breast cancer was based on a randomized, multicenter, open-label, phase II trial, in which 417 patients with HER2-positive, operable, locally advanced or inflammatory breast cancer (T2-4d), were randomly assigned to receive preoperative therapy with either HERCEPTIN® plus TAXOTERE® (Docetaxel), PERJETA® plus HERCEPTIN® and TAXOTERE®, PERJETA® plus HERCEPTIN® or PERJETA® plus TAXOTERE®. Patients in the three drug group received preoperative therapy with PERJETA®, HERCEPTIN® and TAXOTERE® every 3 weeks for a total of 4 cycles and following surgery, all patients received 3 cycles of Fluorouracil, ELLENCE® (Epirubicin), and CYTOXAN® (Cyclophosphamide) – (FEC) IV every 3 weeks and HERCEPTIN® was continued every 3 weeks for a total of one year of therapy. The primary endpoint was pathological Complete Response (pCR) rate defined as the absence of invasive cancer in the breast. The FDA definition of pCR is the absence of invasive cancer in the breast and lymph nodes. All treatment groups were well balanced. Seven percent of patients had inflammatory breast cancer, 32% had locally advanced cancer and 70% had clinically node-positive breast cancer. Forty-seven percent of the patients had hormone receptor-positive disease. The FDA defined pCR rates were 39.3% in the PERJETA® plus HERCEPTIN® and TAXOTERE® group and 21.5% in the HERCEPTIN® plus TAXOTERE® group (P=0.0063). Of Interest, the pCR rates in the three drug group were lower in patients with hormone receptor positive tumors compared to patients with hormone receptor negative tumors. The most common adverse events in the three drug group were alopecia, diarrhea, nausea and neutropenia. Other significant side effects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions and anaphylaxis. Based on clinical studies, for the neoadjuvant treatment of breast cancer, PERJETA® should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer. • Four preoperative cycles of PERJETA® in combination with HERCEPTIN® and TAXOTERE® followed by 3 postoperative cycles of Fluorouracil, ELLENCE® and CYTOXAN® (FEC). • Three preoperative cycles of FEC alone followed by 3 preoperative cycles of PERJETA® in combination with TAXOTERE® and HERCEPTIN®. • Six preoperative cycles of PERJETA® in combination with TAXOTERE®, Carboplatin, and HERCEPTIN® (TCH). Following surgery, patients should continue to receive HERCEPTIN® to complete 1 year of treatment. The accelerated approval by the FDA was based solely on the improved pCR rate with the three drug combination with no demonstrable improvement in event-free survival or overall survival. A confirmatory phase III trial is underway, with results expected in 2016. Gianni L, Pienkowski T, Im YH, et al. Lancet Oncol. 2012;13:25-32

SUMMARY: Bisphosphonates are presently indicated for the treatment of osteoporosis. The approved bisphosphonates in the U.S. include FOSAMAX® (Alendronate), BONIVA® (Ibandronate), ACTONEL® (Risedronate) and RECLAST® (Zoledronic acid). Several trials conducted over the past 2 decades have suggested that bisphosphonates may have anti proliferative effect in patients with breast cancer. Data from several Women's Health Initiative (WHI) studies involving more than 150,000 healthy postmenopausal women, of whom 2216 used oral bisphosphonates, revealed that women taking bisphosphonates for osteoporosis had a 32% reduction in invasive breast cancer. The AZURE investigators conducted a study to determine whether the addition of RECLAST® (Zoledronic acid) to standard adjuvant therapy would improve disease outcomes in patients with early-stage breast cancer. They noted that in the subset analysis, the addition of RECLAST® significantly improved disease free survival and overall survival in postmenopausal patients, independent of estrogen receptor status, tumor stage, and lymph node involvement (N Engl J Med 2011;365:1396-1405). With this background, the authors belonging to the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), conducted a meta-analysis and reviewed data from 15 years of bisphosphonate trials, which included 36 trials of adjuvant bisphosphonates in breast cancer and involved over 17,000 pre and postmenopausal women. RECLAST® (Zoledronic acid) and Clodronate were the most common bisphosphonates used in these trials. The primary outcomes analyzed were time to distant recurrence, local recurrence, new second primary breast cancer (ipsilateral or contralateral), time to first distant recurrence (ignoring any previous locoregional or contralateral recurrences), and breast cancer mortality. Planned subset analyses included site of recurrence, site of first distant metastasis (bone vs other), menopausal status (pre, peri and post) type of bisphosphonate (aminobisphosphonates such as RECLAST® or Clodronate) and drug schedule of bisphosphonate therapy (for bone protection vs advanced cancer). Adjuvant bisphosphonates resulted in a 34% reduction in the risk of bone recurrence (P = 0.00001) and a 17% reduction in the risk of breast cancer death (P =0.004). This benefit was seen regardless of estrogen receptor status, nodal status or whether chemotherapy was used or not. Bisphosphonates had no significant impact on non-breast cancer related deaths, contralateral breast cancer or loco-regional recurrence. In this meta-analysis, all these benefits were only seen in postmenopausal women and premenopausal women had no benefit on any disease outcomes with bisphosphonates. The authors emphasized that low estrogen environment as is seen in postmenopausal women, or women rendered menopausal by suppression of ovarian function is a prerequisite for adjuvant bisphosphonate activity. Based on this large meta-analysis, the authors recommended the use of RECLAST® once every six months or oral Clodronate, where available. Because of paucity of data, they do not recommend the use of weekly dose of oral bisphosphonates, often used to prevent osteoporosis, to achieve these benefits. Coleman R, Gnant M, Paterson A, et al. San Antonio Breast Cancer Symposium 2013; San Antonio, TX. Abstract S4-07.

SUMMARY: NOLVADEX® (Tamoxifen) is a Selective Estrogen Receptor Modulator (SERM), approved by the FDA to also reduce the incidence of breast cancer in women considered to be at high risk (ChemoPrevention). This agent however has been linked to endometrial cancer and thromboembolic phenomenon in some women. ARIMIDEX® is a non-steroidal Aromatase Inhibitor proven to be more efficacious than NOLVADEX® both in metastatic and adjuvant settings. Similar to NOLVADEX®, ARIMIDEX® also prevents the occurrence of new primary tumors in the contralateral breast, in postmenopausal females. With this background, the International Breast Cancer Intervention Study (IBIS) -II trial enrolled 3864 postmenopausal women considered to be at increased risk of breast cancer and randomized them to receive either ARIMIDEX® (Anastrazole) 1 mg QD (N=1920) or Placebo QD (N=1944)for 5 years. Patients were considered to be at high risk if they had a family history of breast cancer, atypical ductal hyperplasia, lobular carcinoma in-situ or dense breast tissue. The median age was 59 years. The primary end point was histologically confirmed Invasive breast cancer or Ductal Carcinoma In- Situ. At a median follow up of 5 years, the incidence of breast cancer in the ARIMIDEX® group was 2% and in the placebo group was 4%. The predicted cumulative incidence of breast cancer after 7 years was 2.8% in the ARIMIDEX® group and 5.6% in the placebo group (HR=0.47; P<0.0001). This represented a 53% reduction in the risk of breast cancer. The adverse events were comparable in both groups with slight increase in the musculoskeletal and vasomotor events noted in the ARIMIDEX® group. The authors concluded that ARIMIDEX® reduced the risk of primary breast cancer by more than 50% in high risk postmenopausal women. Other unrelated studies have shown that acceptance of breast cancer prevention with medications (ChemoPrevention) appeared to be related to education and income, putting emphasis on education and adequate counseling of women, considered to be at high risk. Cuzick J, Sestak I, Forbes JF, et al. The Lancet, Early Online Publication, 12 December 2013

SUMMARY: Exemestane (AROMASIN®) is a steroidal, Aromatase Inhibitor (AI) which has been shown to improve Progression Free Survival (PFS) in postmenopausal patients with ER positive metastatic breast cancer. Patients tend to have limited clinical benefit with subsequent hormonal interventions if their disease recurs or progresses on AI’s. Further, cytotoxic chemotherapy may not be feasible in elderly patients. The PI3K/AKT/mTOR is a complex pathway, essential for cell proliferation, survival and apoptosis (programmed cell death). This pathway is of interest because of its increased activity in malignant cells as a result of amplification or mutation of the genes associated with PI3-kinase (phosphatidylinositol-3 kinase) and AKT, as well as loss of function of PTEN. PTEN normally prevents activation of AKT and its downstream pathways. Elevated ER signaling and breast cancer progression has been associated with activation of this mTOR (mammalian Target Of Rapamycin) pathway. Everolimus (AFINITOR®) is a mTOR inhibitor that has been shown to inhibit ER signaling and restore sensitivity to anti-estrogen therapies. In the phase III BOLERO-2 study, patients with ER positive, advanced breast cancer, who had recurred or progressed on prior therapy with nonsteroidal AI’s such as Anastrozole (ARIMIDEX®) or Letrazole (FEMARA®), had doubling of PFS with a combination of AROMASIN® and AFINITOR® compared to AROMASIN® alone. The authors now report the Safety and Efficacy of AROMASIN® and AFINITOR® combination in 316 patients, 65 years of age or older, out of the 724 patients in the BOLERO-2 study. The median follow up was 18 months. Baseline treatment characteristics were similar in all treatment subsets. The treatment combination resulted in 55% reduction in the risk of disease progression regardless of the age compared to AROMASIN® alone (PFS – 7.8 months vs 3.2 months, HR=0.45, P<0.0001). Further the combination treatment resulted in greater clinical benefit compared to single agent AROMASIN®. Approximately two third of the patients regardless of their age required dose modifications and the most common adverse events in all age groups with similar incidences were stomatitis, rash, fatigue , hyperglycemia and pneumonitis. It is recommended that elderly patients be carefully monitored and toxicities promptly addressed during treatment. The authors concluded that a combination of AROMASIN® and AFINITOR® can provide significant clinical benefit with acceptable toxicities, even in patients 65 years of age or older, thereby delaying the need for chemotherapy. Pritchard KI, Burris HA, Ito Y, et al. Clinical Breast Cancer 2013;13:421-432.

The FDA on September 30, 2013 approved PERJETA&reg; for use in combination with HERCEPTIN&reg; (Trastuzumab) and TAXOTERE&reg; (Docetaxel) for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer. The accelerated approval by the FDA was based solely on the improved pCR rate with the three drug combination with no demonstrable improvement in event-free survival or overall survival. A confirmatory phase III trial is underway, with results expected in 2016. One would hope that the complete response rates would translate into improved survival. Stay tuned.