Tag: Breast Cancer

SUMMARY: 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.

Despite advances in treatment, approximately 30% of patients with node-negative breast cancer and 50% of patients with node-positive breast cancer may relapse within 5 years. This is due to cancer cells shed from primary tumors that migrate to distal sites as Circulating Tumor Cells (CTCs) via the circulatory system. CTCs are therefore precursors of metastatic disease and may not only predict risk of metastatic disease but may also be useful in monitoring treatment efficacy. There have been conflicting reports about the effectiveness of different treatments to reduce CTCs in breast cancer patients, including the different molecular subtypes.

To further address these controversies, the authors conducted a meta-analysis of the published studies which included measurement of CTCs before and after treatment in breast cancer patients, and estimated the benefit of reducing CTC on patient outcomes. Data base searches included 1004 publications and 50 studies conducted between 2009 and 2016 in the US, Europe and Asia. A total of 6712 patients from these studies were eligible for meta-analysis. Enrolled patients had pathologically diagnosed breast cancer, CTCs were detected by any method, including cell capture and quantitative PCR and the patient’s CTC status both pre- and post-therapy was available. The CTC-positive rate was reported using different cut-off values of CTC count and different expression thresholds of epithelial genes (EpCAM, CK18, CK19) using RT-PCR in the various studies.

An overall analysis of the 6712 patients with CTC-positive rate by the random-effects model suggested that treatment intervention significantly decreased CTC-positive rate compared to the baseline (Relative Risk (RR)=0.68, P<0.00001, which meant a 32% reduction in the Relative Risk, compared to baseline values.

Subgroup analyses revealed that when compared to pre-treatment, CTCs were decreased after neoadjuvant treatment (RR=0.65, P=0.006), adjuvant treatment (RR=0.89, P=0.10), treatment in metastatic setting (RR=0.59, P<0.00001) and the combination therapy (RR=0.78, P=0.03). Reduction in CTCs was not seen after surgery (RR=1.27, P=0.42), suggesting that local intervention with surgery does not eliminate CTCs and patients with positive CTCs should receive other therapies after surgery, to decrease the risk of recurrence.

When compared to pre-treatment levels, treatment resulted in significant reduction in CTCs in HER2-positive patients (RR=0.68, P<0.0001) and HER2-negative patients (RR=0.52, P=0.01). This reduction in CTCs was however not noted in patients with triple-negative breast cancer patients (RR=0.38, P=0.29), indicating that current therapies for this group is inadequate and should be further optimized with newer therapies.

More importantly, reduction in CTCs was associated with lower probability of disease progression (P=0.01), longer Progression Free Survival (P<0.0001) and longer Overall Survival (P<0.00001).

It was concluded that based on this large meta-analysis, CTCs can help monitor the effectiveness of treatment and guide subsequent therapies in breast cancer patients. Circulating tumor cell status monitors the treatment responses in breast cancer patients: a meta-analysis. Yan W-T, Cui X, Chen Q, et al. Sci. Rep. 7, 43464; doi: 10.1038/srep43464 (2017).

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. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor 2) negative. TNBC accounts for 15% to 20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. Those who do not achieve a pathological Complete Response tend to have a poor prognosis. It therefore appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway.

Using gene expression profiling, TNBC can be classified into 4 distinct molecular subtypes- two Basal-Like (BL1, BL2), Mesenchymal type (M) and Luminal Androgen Receptor type (LAR). BL1 molecular subtype of TNBCs are characterized by high levels of expression of genes involved in the cell cycle and DNA-damage repair pathways and accounts for up to 18% of TNBCs. These tumors are more sensitive to therapies targeting the DNA-repair pathways such as platinum based chemotherapy and Poly-ADP Ribose Polymerase (PARP) inhibition. BL2 molecular subtype of TNBCs represent 13% of TNBCs and in contrast are characterized by upregulation of growth factor signaling pathways, including the Epidermal Growth Factor (EGF), MET pathways, as well as genes involved in glycolysis and gluconeogenesis. These tumors may better respond to small molecule inhibitors of growth factor pathways. An alternate classification of Basal-Like subtype includes Basal-Like Immune Suppressed (BLIS) which is associated with downregulation of B cell, T cell, and Natural Killer cell immune-regulating pathways, and has the worse prognosis and Basal-Like Immune Activated (BLIA) subtype, which has the best prognosis due to upregulated immune-associated pathways. Mesenchymal TNBCs constitute approximately 10-30% of TNBC tumors and are associated with aberrations in the PI3K/AKT/ mTOR pathway as well as increased angiogenesis and may benefit from agents targeting these pathways. Metaplastic breast cancer belongs to this TNBC group. The Luminal Androgen Receptor (LAR) subtype accounts for approximately 11% of TNBCs. These tumors have a high expression of Androgen Receptor by IHC (Immuno HistoChemistry) and benefit from Androgen Receptor blockade and do not respond to cytotoxic chemotherapy.

Ipatasertib is a highly selective oral ATP-competitive, small-molecule, AKT inhibitor and sensitivity to Ipatasertib has been associated with high levels of phosphorylated AKT, PTEN protein loss or genetic mutations in PTEN, and PIK3CA mutations. KRAS and BRAF mutations are typically associated with resistance to Ipatasertib. It is estimated that approximately 50% of TNBCs have deficient expression of the tumor suppressor PTEN, which is associated with a higher degree of AKT pathway activation Preclinical studies showed synergy between Ipatasertib and Taxanes. Because of the high prevalence of PI3K/AKT pathway activation in TNBCs, the authors in this study evaluated the benefit of a combination of Ipatasertib and Paclitaxel as first line therapy, for TNBC.

The LOTUS trial is a randomized, placebo controlled, double blind, phase II study in which 124 treatment naïve patients with inoperable, locally advanced or metastatic Triple Negative Breast Cancer were randomly assigned (1:1) to receive Paclitaxel 80 mg/m2 IV Days 1, 8, 15 of a 28 day cycle in combination with either Ipatasertib 400 mg PO daily (N=62) or placebo (N=62), administered on days 1-21 of each 28 day cycle. Treatment was continued until disease progression or unacceptable toxicity. Patients in this study were stratified based on expression of the PTEN tumor suppressor gene and alteration of PIK3CA/AKT1/PTEN in their tumors. The co-primary endpoints were Progression Free Survival (PFS) in the intent-to-treat population and Progression Free Survival in the PTEN-low population. Secondary endpoints included Objective Response Rate and Duration of Response. The median follow up was 10.3 months.

It was noted that the median PFS in the intent-to-treat population was 6.2 months with Ipatasertib versus 4.9 months with placebo (HR=0.60; P=0.037). In the 48 patients with low PTEN expression tumors, the median PFS however was 6.2 months with Ipatasertib and 3.7 months with placebo (HR=0.59; P=0.18), and this was not statistically significant. The PFS benefit was more pronounced in the patient group with PIK3CA/AKT1/PTEN-altered tumors, with a median PFS of 9.0 months in the Ipatasertib group versus 4.9 months in the placebo group (HR=0.44; P=0.041). The most common grade 3/4 adverse events in the Ipatasertib group were diarrhea and neutropenia.

The authors concluded that Ipatasertib prolonged Progression Free Survival compared to placebo and is the first study supporting AKT-targeted therapy for Triple Negative Breast Cancer, supporting the use of gene expression profiling in this heterogeneous malignancy. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Kim S, Dent R, Im S, et al on behalf of the LOTUS investigators. The Lancet Oncology 2017;18:1360-1372

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. Benign Breast Disease (BBD) is an important risk factor for the later development of breast cancer in either breast. With the routine use of mammography, the identification of BBD has become more common, and this has in turn enabled the calculation of breast cancer risk. The Breast Cancer Risk Assessment Tool which is an interactive tool designed by researchers at the National Cancer Institute (NCI) and the National Surgical Adjuvant Breast and Bowel Project (NSABP) to estimate a woman's risk of developing invasive breast cancer, utilizes the number of breast biopsies and atypical hyperplasia, in addition to other factors, to estimate women’s risk of developing breast cancer. Benign Breast Disease (BBD) encompasses a variety of histologic entities. FibroCystic Changes (FCCs) constitute the most frequent benign disorder of the breast. FCCs may be multifocal and bilateral and women usually present with symptoms of breast pain and tender nodularities in breasts. Hormonal imbalance, with estrogen predominance over progesterone, has been implicated as an important contributing factor in its development. Fibrocystic changes are usually subdivided into nonproliferative lesions, proliferative lesions without atypia, and proliferative lesions with atypia (atypical hyperplasia). Proliferative or atypical lesions are associated with an increased risk of breast cancer. However a significant majority of breast biopsies (about 70%) show nonproliferative lesions.

Breast cancer is heterogeneous malignancy and using global gene expression analyses, 6 breast cancer intrinsic subtypes have been established. They include Luminal A, Luminal B, HER2-enriched, Claudin-low, Basal-like, and a Normal breast-like group. Triple Negative Breast Cancer (TNBC) accounts for 12–24% of all breast carcinomas and is negative for Estrogen Receptor (ER), Progesterone Receptor (PR), and HER2. There is a 2 fold increase in the incidence of TNBC among African American (AA) women compared with White American (WA) women and is a surrogate for the inherently aggressive Basal-like breast cancer subtype. This group has the worse prognosis compared to other breast cancer subtypes. Basal-like breast cancer sub-type is also a marker of hereditary breast cancer susceptibility. Multiparity may increase the risk of TNBC and reduce the likelihood of developing ER-positive breast cancer. Triple Negative Breast Cancer (TNBC) compared with non-TNBC, likely arises from different pathogenetic pathways. NF-κB pathway, which controls immune response, angiogenesis, the cell cycle, extracellular matrix degradation, and apoptosis, may represent a key regulator of TNBC. Activation of PI3K/AKT pathway in turn, has been implicated in oncogenic transformation.

Benign breast disease (BBD) has been associated with increased risk for ER positive/non-TNBC. The purpose of this study was to determine whether African American (AA) identity is associated with TNBC among a cohort of both AA and White American (WA) women, who were initially diagnosed with BBD. The authors in this study conducted a retrospective analysis of a cohort comprising 2588 African American women and 3566 White American women aged between 40 and 70 years, with a biopsy-proven Benign Breast Disease. This data was obtained from the Pathology Information System of Henry Ford Health System (HFHS), an integrated multihospital and multispecialty health care system in Detroit, Michigan. These individuals had breast biopsies performed between January 1, 1994, and December 31, 2005 and data analysis was performed from November 1, 2015, to June 15, 2016. Patients with prior breast cancer and those with breast cancer diagnosed within 6 months of BBD biopsy were excluded. Benign Breast Disease was classified as fibrocystic/proliferative/hyperplasia without atypia, with atypia, or with lobular carcinoma in situ. The mean follow up was 10.2 years for both AA patients and WA patients.

It was noted that more than 75% of the subsequent breast cancers in each subset were Ductal Carcinoma in Situ (DCIS) or Stage I. Among the African American (AA) patients who developed subsequent invasive breast cancer, 24.2% developed TNBC compared with 7.4% of the White American (WA) patients who developed subsequent invasive breast cancers (P=0.01). The 10 year probability estimate for developing TNBC was 0.56% for AA patients and 0.25% for WA patients.

The authors concluded that in this largest analysis to date of TNBC and its relationship to racial/ethnic identity and Benign Breast Disease as risk factors, African American identity persisted as a significant risk factor for Triple Negative Breast Cancer, suggesting that African American identity is associated with inherent susceptibility for TNBC pathogenetic pathways. This important finding should be taken into consideration, when discussing chemoprevention strategy among African American women with Benign Breast Diseases. Association Between Benign Breast Disease in African American and White American Women and Subsequent Triple-Negative Breast Cancer. Newman LA, Stark A, Chitale D, et al. JAMA Oncol. 2017;3:1102-1106.

SUMMARY: The FDA on September 28, 2017, approved VERZENIO® (Abemaciclib) in combination with FASLODEX® (Fulvestrant) for women with Hormone Receptor positive (HR-positive), HER2-negative, advanced or metastatic breast cancer, with disease progression following endocrine therapy. In addition, VERZENIO® was approved as monotherapy for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. 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.

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. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. 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. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.

VERZENIO® is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against cyclin D1/CDK 4 and cyclin D3/CDK 6, in enzymatic assays. VERZENIO® in the phase I trials was noted to be active in HR-positive, metastatic breast cancer, as monotherapy as well as in combination with FASLODEX®. Based on this preliminary data, two clinical trials, MONARCH 1 and MONARCH 2, were conducted.

The approval of VERZENIO® as monotherapy in HR-positive, metastatic breast cancer was based on MONARCH 1, which is a a single-arm, open-label, phase II, multicenter study, which enrolled women with measurable HR-positive, HER2-negative metastatic breast cancer, whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received one or two prior chemotherapy regimens in the metastatic setting. This trial included 132 patients who received VERZENIO® 200 mg orally twice daily on a continuous schedule, until disease progression. The Objective Response Rate was 19.7%, with a median response duration of 8.6 months.

The approval of VERZENIO® in combination with FASLODEX® was based on MONARCH 2, which is an international, double-blind, phase III study in which 669 patients were randomized in a 2:1 ratio to receive either VERZENIO® plus FASLODEX® (N=446) or placebo plus FASLODEX® (N=223). Enrolled patients had HR-positive, HER2-negative metastatic breast cancer, with disease progression while receiving neoadjuvant or adjuvant endocrine therapy, within 12 months of adjuvant endocrine therapy, or while receiving endocrine therapy for metastatic breast cancer. Patients must not have received more than one endocrine therapy or any prior chemotherapy for metastatic breast cancer. Randomized patients received either VERZENIO® 150 mg or placebo orally twice daily plus FASLODEX® 500 mg IM on Day 1 and Day 15 of cycle 1 and then on Day 1 of cycle 2 and beyond (28-day cycles). Treatment was continued until disease progression or unmanageable toxicities. The mean patient age was 60 years, 82% of patients were postmenopausal, 72% had measurable disease, 56% had visceral disease, and 25% had primary endocrine therapy resistance. About 60% of patients had received chemotherapy in the adjuvant or neoadjuvant setting and 69% of the patients had prior therapy with Aromatase Inhibitors (AI). The Primary end point was Progression Free Survival (PFS), and Secondary end points included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response, Clinical Benefit Rate, Quality of Life, and safety.

The median PFS for the group receiving VERZENIO® plus FASLODEX® was 16.4 months compared with 9.3 months for those taking placebo with FASLODEX® (HR= 0.55; P<0.0001). In patients with measurable disease, the Objective Response Rate for the group receiving VERZENIO® plus FASLODEX® was 48.1% compared to 21.3% in the placebo with FASLODEX® treated patients. The most common adverse events in the VERZENIO® versus placebo groups were diarrhea neutropenia, nausea and fatigue.

It was concluded that a combination of VERZENIO® plus FASLODEX® significantly improved Progression Free Survival and Objective Response Rates, with a tolerable safety profile, in patients with Hormone Receptor-positive and HER 2-negative metastatic breast cancer who progressed while receiving endocrine therapy. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. Sledge GW, Toi M, Neven P, et al. DOI: 10.1200/JCO.2017.73.7585 Journal of Clinical Oncology 35, no. 25 (September 2017) 2875-2884.

MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. Dickler MN, Tolaney SM, Rugo HS, et al. J Clin Oncol 34, 2016 (suppl; abstr 510).

In the US, about 33 million screening mammograms are performed each year. Currently, the major national health care organizations in the US have different recommendations for screening mammography which has led to some confusion and emotional counterarguments. These several different recommendations include 1) Annual screening at ages 40 to 84 years. 2) Annual screening at ages 45 to 54 years and then biennially at ages 55 to 79 years. 3) Biennial screening at ages 50 to 74 years.

In a recently published study (CANCER,  August 21, 2017), it was noted  that the greatest breast cancer-specific mortality reduction was achieved with annual screening of women starting at age 40 years, saving 29,369 lives from breast cancer. This is the first study to compare the three most widely discussed recommendations for screening mammography, head to head.

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. In the US, about 33 million screening mammograms are performed each year.

Currently, the major national health care organizations in the US have different recommendations for screening mammography which has led to some confusion and emotional counterarguments. These several different recommendations include 1) Annual screening at ages 40 to 84 years 2) Annual screening at ages 45 to 54 years and then biennially at ages 55 to 79 years 3) Biennial screening at ages 50 to 74 years.

To address this varied recommendations and help women make informed decisions regarding mammography screening, the authors used computer modeling (CISNET models) to assess the three major screening mammography recommendations, and estimate the number of breast cancer deaths that might be prevented with the different screening mammography schedules. Cancer Intervention and Surveillance Modeling Network (CISNET) is a consortium of NCI-sponsored investigators who use statistical modeling to improve understanding of cancer control interventions in prevention, screening and treatment, and their effects on population trends in incidence and mortality. CISNET has been cited by the International Society Pharmacoeconomics and Outcomes Research (ISPOR) Task Force on Good Modeling Practices for its role in establishing a forum that enables researchers to compare results and articulate reasons for discrepancies.

It was noted in this study that the mean mortality reduction in breast cancer-specific deaths was greatest with the recommendation of annual screening at ages 40 to 84 years (39.6%), which meant that 29,369 lives were saved from breast cancer, compared with the recommendation of screening annually at ages 45 to 54 years, then biennially at ages 55 to 79 years (30.8%), which meant that 22,829 were lives saved from breast cancer, and the recommendation of biennial screening at ages 50 to 74 years (23.2%) which meant that 17,153 lives were saved from breast cancer.

The study also took into consideration risks associated with screening, including callbacks for additional imaging following indeterminate or suspicious mammographic finding and in some cases, a breast biopsy, only to find out that the findings were benign. The authors commented that the average woman in her 40s getting annual screening can expect additional and unnecessary screening about once every 12 years and unnecessary breast biopsy recommendations once every 150 years. Other rare risks with screening mammography include breast cancer that could be missed and breast cancer caused by mammogram radiation.

It was concluded that based on the CISNET models, the greatest breast cancer-specific mortality reduction is achieved with annual screening of women starting at age 40 years. They added that this is the first study to compare the three most widely discussed recommendations for screening mammography, head to head. These findings will guide women and their Health Care Providers in deciding when to begin screening mammography and how often to get screened. Comparison of recommendations for screening mammography using CISNET models. Arleo EK, Hendrick E, Helvie MA, et al. CANCER; Published Online: August 21, 2017. http://doi.wiley.com/10.1002/cncr.30842

SUMMARY: The FDA on July 17, 2017 approved NERLYNX® (Neratinib) for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant Trastuzumab (HERCEPTIN®)-based 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, 255,180 new cases of invasive breast cancer will be diagnosed in 2017 and over 41,070 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.

The approval of NERLYNX® was based on ExteNET trial, which 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 Primary endpoint 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, within two years of follow up. The median follow up was 2 years.

In the updated analysis, the two year iDFS was 94.2% in patients treated with NERLYNX® compared with 91.9% in those receiving placebo (HR 0.66; P=0.008). Patients with ER positive breast cancer were noted to have greater benefit. 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.

It was concluded 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. Longer follow up will hopefully address if there is an Overall Survival benefit with this treatment intervention. 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 patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial Chan A, Delaloge S, Holmes FA, et al. The Lancet Oncology 2016; 17:367- 377