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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. Circulating Tumor Cells (CTCs) are epithelial cells that are shed into the circulation from a primary or metastatic tumor. After being shed, CTCs can remain in the circulation or undergo apoptosis. Evaluation of CTCs during the course of disease has prognostic value. Because of the very low concentrations of CTCs (1 CTC in the background of millions of normal hematopoietic cells) in the peripheral blood, different technologies have been developed that will allow enrichment and detection of these CTCs. One such technology is the CELLSEARCH® system which is the first FDA-approved test for CTC assessment, in the peripheral blood of patients with breast cancer. This automated system is able to enrich the peripheral blood sample with CTCs and the cells then are fluorescently stained for CytoKeratins (CK8,18 and 19), Common Leukocyte Antigen (CD45) and a nuclear dye (DAPI). CTCs are identified when they are CK positive, CD45 negative and DAPI positive. In essence, CTC assessment is a real time, peripheral blood evaluation (“Liquid Biopsy”) in breast cancer patients.

In women with Hormone Receptor (HR)-positive breast cancer, late recurrences occurring 5 or more years after diagnosis, account for approximately 50% of recurrences. In a meta-analysis from the EBCTCG (Early Breast Cancer Trialists’ Collaborative Group) group, the 10-year risk of recurrence after 5 years of endocrine therapy was found to be 5% in patients with node negative breast cancer, 10% in patients with 1-3 positive lymph nodes, and 22% in patients with 4-9 positive lymph nodes. Late recurrence in patients with HR-positive breast cancer has therefore become a major concern, as this risk for recurrence and death from breast cancer can be ongoing for at least 20 years after the original diagnosis..

The blood and tumor samples of patients are valuable for research and allow the exploration of possible tumor and host-related factors contributing to recurrence. The Coalition of Cancer Cooperative Groups, a non-profit member organization of the National Cancer Institute-sponsored Cooperative Groups, in 2013, created the North American Breast Cancer Groups (NABCG) Biospecimen Bank for Determinants of Late Relapse in Operable Breast Cancer. The purpose for the collection and analysis of samples is, to improve our understanding of breast cancer, and identify which patients are most likely to benefit from specific therapies. The NABCG Biospecimen Bank remains a unique resource of archived primary and metastatic tumor tissue, blood, and DNA, collected from more than 15,000 women, who participated in two large cooperative group cancer treatment trials, TAILORx and E5103.

The authors in this analysis included 546 patients with HER-2-negative, stage II to stage III breast cancer from the E5103 clinical trial, with no clinical evidence of recurrence between 4.5 to 7.5 years following their initial diagnosis. ECOG-ACRIN clinical trial E5103 is a randomized phase III trial, which evaluated the addition of Bevacizumab (AVASTIN®), a Vascular Endothelial Growth Factor (VEGF) inhibitor, to adjuvant chemotherapy following surgery, in patients with lymph node-positive or high-risk, lymph node-negative breast cancer. All patients had undergone surgery and adjuvant chemotherapy as well as endocrine therapy for at least 5 years, if hormone receptor positive. The CTCs from the blood samples of these patients were measured using the CELLSEARCH® CTC assay. None of the patients had clinical evidence of recurrence at the time of this analysis. More than half of the patients (56%) were 50 years or older, 59% of the patients had a tumor 2 cm or larger, 73% had positive lymph nodes and 65% had Hormone Receptor (HR) positive disease. This Primary endpoint of this study was time to recurrence and the primary focus in this analysis was on the group with Hormone Receptor positive disease.

After a median follow up of 1.6 years, 4.8% of patients had a positive CTC assay result overall (1 or more cells/7.5 mL in the blood). Among those with Hormone Receptor positive breast cancer, 5.1% had a positive CTC assay result whereas positive CTC assay result was noted in 4.1% of patients with hormone receptor negative disease. Of the 353 patients with HR-positive disease in this analysis, 4% had a recurrence whereas only 0.5% with HR-negative disease had a local recurrence. The Hazard Ratio for patients with CTC negative results compared with CTC positive results was 21.7 (P<0.001). A positive CTC assay result was associated with a nearly 21.7 fold increased risk of breast cancer recurrence in patients with HR-positive disease. A positive CTC assay was not associated with recurrence in the HR-negative group. The Positive Predictive Value of a positive CTC assay for recurrence at 2 years, in patients with HR-positive disease was 35%, and the Negative Predictive Value for patients in this cohort was 98%.

It was concluded that detection of positive Circulating Tumor Cells in the blood, 5 years after breast cancer diagnosis, was associated with an increased risk for late recurrence, in women with HR-positive, HER2-negative breast cancer. Sparano JA, O’Neill A, Alpaugh K, et al. Circulating tumor cells and late recurrence of breast cancer. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-03.

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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% 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 and adjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early breast cancer. Nonetheless, approximately 25% of patients will develop recurrent disease within 10 years following this adjuvant intervention. Extending the duration of adjuvant HERCEPTIN® therapy or adding TYKERB® (Lapatinib), a Tyrosine Kinase Inhibitor that targets HER1 and HER2, has not improved outcomes.

NERLYNX® is a potent, irreversible, oral Tyrosine Kinase Inhibitor, of HER1, HER2 and HER4 (pan-HER inhibitor).NERLYNX® interacts with the catalytic domain of HER1, HER2, and HER4 and blocks their downstream signaling pathways, resulting in decreased cell proliferation and increased cell death. Clinical data has suggested that NERLYNX® has significant activity in suppressing HER-mediated tumor growth and is able to overcome tumor escape mechanisms experienced with current HER2-targeted and chemotherapeutic agents. It has been well known that hormone receptor positive breast cancer patients, who are also HER2-positive, have relative resistance to hormone therapy. Preclinical models had suggested that the addition of NERLYNX® could improve responses in ER positive, HER2-positive breast cancer patients. Further, NERLYNX® has clinical activity in patients with HER2-positive metastatic breast cancer.

ExteNET trial is a multicentre, randomized, double-blind, placebo-controlled, phase III study, in which the efficacy and safety of 12 months of NERLYNX® after HERCEPTIN®-based adjuvant therapy was evaluated, in patients with early stage HER2-positive breast cancer. Patients with early stage HER2-positive breast cancer (N=2,840), and within two years of completing adjuvant HERCEPTIN®, were randomized in a 1:1 ratio to receive either oral NERLYNX® 240 mg per day (N=1420) or placebo (N=1420), for one year. Patients were stratified by hormone receptor status, nodal status (0, 1-3, or 4 or more), and HERCEPTIN® adjuvant regimen (sequentially versus concurrently with chemotherapy). The authors had previously reported that NERLYNX® when given for 12 months after chemotherapy and HERCEPTIN®-based adjuvant therapy, to women with HER2-positive breast cancer, significantly improved 2-year invasive Disease Free Survival.

They now reported updated efficacy outcomes, from a protocol-defined 5-year follow-up sensitivity analysis, and long-term toxicity findings. The predefined endpoint of the 5-year analysis was invasive Disease Free Survival (iDFS), defined as the time between the randomization date to the first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distant recurrence, or death from any cause. The median follow up was 5.2 years.

It was noted that patients in the NERLYNX® group had significantly fewer invasive Disease Free Survival events, than those in the placebo group (HR=0.73; P=0.0083). The 5-year invasive Disease Free Survival was 90.2% in the NERLYNX® group and 87.7% in the placebo group. The most common grade 3-4 adverse events associated with NERLYNX® were diarrhea, vomiting and nausea. Patients can experience diarrhea early, in the first 2 or 3 days and this can be alleviated using antidiarrheal prophylaxis with Loperamide, initiated with the first dose of NERLYNX® and continued for the first 2 months of treatment and as needed thereafter. There was no evidence of long-term toxicities associated with NERLYNX®, when compared to placebo.

It was concluded that at a median follow up of 5 years, NERLYNX® when given for 12 months after chemotherapy and HERCEPTIN®-based adjuvant therapy, to women with HER2-positive breast cancer, significantly reduced the proportion of clinically relevant breast cancer relapses that might lead to death, such as distant and locoregional recurrences outside the preserved breast. This benefit was seen without increase in the risk of long term toxicity. Overall Survival data will be available at a later date. NERLYNX® is the first TKI approved by the FDA, shown to reduce the risk for disease recurrence, in patients with early stage HER2-positive breast cancer. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Martin M, Holmes FA, Ejlertsen B, et al. for the ExteNET Study Group. Lancet Oncol 2017;18:1688-1700

SUMMARY: The FDA on January 12, 2018, granted regular approval to LYNPARZA® (Olaparib), a Poly ADP-Ribose Polymerase (PARP) inhibitor, for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer, who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. This is the first FDA-approved treatment for patients with gBRCAm HER2-negative metastatic breast cancer. Patients with Hormone Receptor (HR) positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Patients must be selected for therapy based on an FDA-approved companion diagnostic for LYNPARZA®.

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, 266,120 new cases of invasive breast cancer are expected to be diagnosed in 2018 and about 40,920 women are expected to die of the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.

The PARP (Poly ADP Ribose Polymerase) family of enzymes, which include PARP1 and PARP2 repair damaged DNA. LYNPARZA® is a PARP enzyme inhibitor that causes cell death in tumors that already have a DNA repair defect, such as those with BRCA1 and BRCA2 mutations. The FDA approved LYNPARZA® in 2014 as monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated advanced ovarian cancer.

The present approval was based on data from OlympiAD, a randomized, open-label, phase III study that evaluated the efficacy and safety of LYNPARZA® compared with physician’s choice of standard single agent chemotherapy, in patients with HER2-negative metastatic breast cancer, with inherited, germline BRCA mutations. In this study, 302 patients were randomized in a 2:1 ratio to receive LYNPARZA® tablets 300 mg PO BID (N=205) or physician’s choice of standard chemotherapy (N=97). The later included 21-day cycles of either XELODA® (Capecitabine) 2500 mg/m2 orally on days 1-14, NAVELBINE® (Vinorelbine) 30 mg/m2 IV days 1 and 8 or HALAVEN® (Eribulin)1.4 mg/m2 IV days 1 and 8. Treatment was continued until disease progression or unacceptable toxicity. The median age was 44 years, and all patients had received prior chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients in this study were stratified based on prior use of chemotherapy for metastatic disease, Hormone Receptor status (HR positive versus triple negative), and previous use of platinum-based chemotherapy. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), time to second progression or death, Objective Response Rate (ORR) and effect on health-related Quality of Life.

At a median follow up of about 14 months, the median PFS was 7 months in the LYNPARZA® group versus 4.2 months with standard chemotherapy (HR=0.58; P=0.0009), suggesting a 42% reduced risk of cancer progression in the LYNPARZA® group compared to those who received chemotherapy. Following disease progression, the time to second progression (which meant duration of time before the cancer worsened again), was also longer in the LYNPARZA® group (HR 0.57), suggesting that recurrent disease was not more aggressive following progression on LYNPARZA®. The ORR was 60% and 29% in LYNPARZA® and chemotherapy groups respectively. Severe side effects were more common in chemotherapy treated patients (50%) compared with LYNPARZA® group (37%). The most common side effects in the LYNPARZA® group included nausea, fatigue and cytopenias, whereas rash on hands and feet were most common in the chemotherapy group.

The authors concluded that LYNPARZA® monotherapy significantly improved Progression Free Survival in HER2-negative metastatic breast cancer patients, with inherited germline BRCA mutations, compared to standard chemotherapy. This “proof of the principle” study demonstrated that breast cancers with defects in a specific DNA damage repair pathway are sensitive to targeted therapy and this is the first of several phase III studies with PARP inhibitors that are underway. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). Robson ME, Im S-A, Senkus E, et al. J Clin Oncol 35, 2017 (suppl; abstr LBA4).

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. It is estimated that 252,710 new cases of invasive breast cancer and 63,410 new cases of non-invasive breast cancer will be diagnosed in women in 2017 and 40,610 women are expected to die from the disease. It is estimated that approximately 140 million women worldwide use hormonal contraception and this number accounts for approximately 13% of women between the ages of 15 and 49 years. The use of hormonal contraception has been on the rise.

Estrogen promotes the development of breast cancer. Previous published studies had shown positive associations between the use of oral contraceptives and breast cancer risk, but the results have been inconsistent from no increase in risk to a 20-30% increase in risk. Further, unlike contemporary hormonal contraception, oral contraceptives in the past contained a higher estrogen dose in the combined estrogen/progestin hormonal contraceptives, and the higher dose of estrogen has been implicated in the development of breast cancer. Contemporary products with new progestins and new routes of delivery (intrauterine system, contraceptive patches, vaginal rings, progestin-only implants, and injections) has raised new concerns, with some studies suggesting that the addition of progestin appears to increase the risk of breast cancer among postmenopausal women who receive hormone therapy. There is evidence to suggest that use of hormonal contraception at a young age may confer a higher risk of breast cancer than initiation of use later in life.

This Danish study, using their national registry, reported the risk of invasive breast cancer risk among women of reproductive age, who were using currently available hormonal contraception. This prospective cohort study conducted in Denmark included 1.8 million women between 15-49 years of age, who did not have a diagnosis of cancer or venous thromboembolism, and who had not received treatment for infertility. Individually updated information about the use of hormonal contraception, breast cancer diagnoses, and potential contributing factors, was obtained from nationwide registries.

It was noted that when compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (20% higher than average). This risk increased from 1.09 (9% higher than average) with less than 1 year of use to 1.38 (38% higher than average) with more than 10 years of hormonal contraception use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer continued to be higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives, with a relative risk of 1.21 (21% higher than average). Outcomes in this study however, could not be adjusted for age at menarche, breast feeding, alcohol consumption, physical activity or Body Mass Index.

It was concluded from this large study population that, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use. Additionally, these results unequivocally suggest that no hormonal contraceptives are free of risk. Contemporary Hormonal Contraception and the Risk of Breast Cancer. Mørch LS, Skovlund CW, Hannaford PC, et al. N Engl J Med 2017; 377:2228-2239

It is estimated that approximately 140 million women worldwide use hormonal contraception and this number accounts for approximately 13% of women between the ages of 15 and 49 years. Estrogen promotes the development of breast cancer and there is evidence to suggest that use of hormonal contraception at a young age may confer a higher risk of breast cancer than initiation of use later in life.
In a recent study (N Engl J Med 2017; 377:2228-2239), it was noted that the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (20% higher than average). This risk increased from 1.09 (9% higher than average) with less than 1 year of use to 1.38 (38% higher than average) with more than 10 years of hormonal contraception use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer continued to be higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives, with a relative risk of 1.21 (21% higher than average). These findings unequivocally suggest that no hormonal contraceptives are free of risk.

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. It is estimated that 252,710 new cases of invasive breast cancer and 63,410 new cases of non-invasive breast cancer will be diagnosed in women in 2017 and 40,610 women are expected to die from the disease.

It has been well established that treatment with 5 years of endocrine therapy in early stage, Estrogen Receptor (ER) positive breast cancer, significantly reduces the risks of locoregional and distant recurrence, contralateral breast cancer, death from breast cancer, and therefore death from any cause. Extended adjuvant endocrine therapy with either Tamoxifen or an Aromatase Inhibitor (AI) beyond 5 years can further reduce breast cancer recurrence. This however can result in treatment related side effects. Therefore, when considering extended adjuvant endocrine therapy beyond 5 years, the potential benefits should be weighed against the associated risk with such therapy. The absolute benefit of continuing endocrine therapy after 5 years depends on the absolute risk of later recurrence, if patient’s receives no further therapy.

The authors in this publication reported the influence of original tumor characteristics, on the incidence of breast cancer outcomes, over a 20 year period. This meta-analysis included data from 88 trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) database of randomized trials, involving 62,923 women with ER-positive breast cancer, who were disease-free after 5 years of adjuvant endocrine therapy. Data was analyzed from women who had T1 disease (Tumor diameter 2 cm or less) or T2 disease (Tumor diameter more than 2 cm up to 5 cm), no positive nodes (N0), 1-3 positive nodes (N1-3), 4-9 positive nodes (N4-9), and no distant metastases. The authors then assessed the associations of Tumor diameter and Nodal status (TN), tumor grade, and other factors with patients’ outcomes, during the period from 5 to 20 years.

It was noted that distant breast cancer recurrences occurred at a steady rate for at least another 15 years after completing 5 years of adjuvant hormonal treatment. The risk of distant recurrence strongly correlated with the original Tumor diameter and Nodal status (TN status).

Among women with T1 disease, the risk of distant recurrence was 13% in those with T1N0 disease, 20% in those with T1N1-3 disease and 34% in those with T1N4-9 disease. Even in those women with low grade T1N0 breast cancer, the absolute risk of distant recurrence from 5-20 years was 10%.

Among those with T2 disease, the risk of distant recurrence was 19% with T2N0 disease, 26% with T2N1-3 disease, and 41% with T2N4-9 disease. TN status was also a strong determinant of locoregional recurrence, but not predictive for contralateral breast cancer.

There was a strong association of tumor grade and Ki-67 status with the risk of distant recurrence during the first 5 years but had limited additional prognostic relevance during years 5-20. Similarly, patients with negative Progesterone Receptor (PR) had a worse prognosis during the first 5 years but not thereafter.

The authors concluded that even after 5 years of adjuvant endocrine therapy, women with ER-positive, early stage breast cancer, continue to be at risk for recurrence and death from breast cancer, for at least 20 years after the original diagnosis. This risk varies from 10-41% and is strongly dependent on TN status at the time of initial diagnosis. Even those with low-grade T1N0 disease were at an appreciable risk of distant recurrence. Extended adjuvant endocrine therapy beyond 5 years may reduce this risk, and this study highlights the need for new approaches to reduce late recurrence. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. Pan H, Gray R, Braybrooke J, et al. for the EBCTCG. N Engl J Med 2017; 377:1836-1846