Jesus Anampa

Progress in adjuvant chemotherapy for breast cancer: an overview

Breast cancer is the most common cause of cancer and cancer death worldwide. Although most patients present with localized breast cancer and may be rendered disease-free with local therapy, distant recurrence is common and is the primary cause of death from the disease. Adjuvant systemic therapies are effective in reducing the risk of distant and local recurrence, including endocrine therapy, anti-HER2 therapy, and chemotherapy, even in patients at low risk of recurrence. The widespread use of adjuvant systemic therapy has contributed to reduced breast cancer mortality rates. Adjuvant cytotoxic chemotherapy regimens have evolved from single alkylating agents to polychemotherapy regimens incorporating anthracyclines and/or taxanes. This review summarizes key milestones in the evolution of adjuvant systemic therapy in general, and adjuvant chemotherapy in particular. Although adjuvant treatments are routinely guided by predictive factors for endocrine therapy (hormone receptor expression) and anti-HER2 therapy (HER2 overexpression), predicting benefit from chemotherapy has been more challenging. Randomized studies are now in progress utilizing multiparameter gene expression assays that may more accurately select patients most likely to benefit from adjuvant chemotherapy.

Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

Chemotherapy induces prometastatic changes in breast cancer, reversible by TIE2 or MENA inhibition. Closing the door to cancer cells Breast cancer is one of the most common tumor types, and metastasis greatly increases the risk of death from this disease. By studying the process of intravasation or entry of cells into the vasculature, Karagiannis et al. discovered that, in addition to killing tumor cells, chemotherapy treatment can also increase intravasation. Groups of cells collectively known as tumor microenvironment of metastasis (TMEM) can serve as gateways for tumor cells entering the vasculature, and the authors discovered that several types of chemotherapy can increase the amounts of TMEM complexes and circulating tumor cells in the bloodstream. The researchers also determined that a drug called rebastinib can interfere with TMEM activity and help overcome the increased risk of cancer cell dissemination. Breast cancer cells disseminate through TIE2/MENACalc/MENAINV-dependent cancer cell intravasation sites, called tumor microenvironment of metastasis (TMEM), which are clinically validated as prognostic markers of metastasis in breast cancer patients. Using fixed tissue and intravital imaging of a PyMT murine model and patient-derived xenografts, we show that chemotherapy increases the density and activity of TMEM sites and Mena expression and promotes distant metastasis. Moreover, in the residual breast cancers of patients treated with neoadjuvant paclitaxel after doxorubicin plus cyclophosphamide, TMEM score and its mechanistically connected MENAINV isoform expression pattern were both increased, suggesting that chemotherapy, despite decreasing tumor size, increases the risk of metastatic dissemination. Chemotherapy-induced TMEM activity and cancer cell dissemination were reversed by either administration of the TIE2 inhibitor rebastinib or knockdown of the MENA gene. Our results indicate that TMEM score increases and MENA isoform expression pattern changes with chemotherapy and can be used in predicting prometastatic changes in response to chemotherapy. Furthermore, inhibitors of TMEM function may improve clinical benefits of chemotherapy in the neoadjuvant setting or in metastatic disease.

Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

Dual inhibition of MDMX and MDM2 by an α-helical p53-stapled peptide (ALRN-6924) results in robust antitumor activity in acute myeloid leukemia. A new staple of leukemia treatment? As suggested by their name, tumor suppressor genes prevent tumorigenesis, and their expression or activity is often lost in cancer cells. One of the best known tumor suppressors is p53, which is inactivated in a variety of cancer types, often through up-regulation of its endogenous suppressors. Despite numerous attempts to reactivate p53 by a variety of approaches, none have successfully advanced beyond clinical trials thus far. Now, Carvajal et al. applied yet another tactic to restore p53 activity by using a stapled peptide to inactivate both of its endogenous inhibitors, for situations where the tumor suppressor is inactive but not completely lost. The authors demonstrated the effectiveness of this approach in human acute myeloid leukemia using in vitro and in vivo models, along with preliminary testing in a patient with leukemia. The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell–enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.

New agents for the management of resistant metastatic breast cancer

ABSTRACT Introduction: Metastatic breast cancer (MBC) is an incurable disease and treatment is directed towards symptom palliation and survival prolongation. Treatment selection in patients is based on tumor biology, age, comorbidities, performance status, tumor burden, and prior treatment history. Areas covered: This present review summarizes the recent treatment strategies in the management of MBC, highlighting regimens after first-line therapy. Topics discussed include new strategies for endocrine therapy, anti-HER2 therapy, and promising strategies for the management of triple negative breast cancer. Expert opinion: MBC is a heterogeneous entity and despite recent advances, there is significant room for improvement of treatment beyond first-line therapies. Combination regimens that can maximize clinical efficacy while minimizing toxicities are required. Current investigation approaches in advanced stages of clinical development include immunoconjugates, immune checkpoint blockade, novel cyclin-dependent-kinase inhibitors, and PARP inhibitors for MBC associated with germline BRCA mutations. We recommend that every patient with MBC should be evaluated for clinical trial options.

Anthracycline Use for Early Stage Breast Cancer in the Modern Era: a Review

Opinion statementAnthracycline-based regimens have been an important treatment component for patients with breast cancer. As demonstrated in the last Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis, anthracycline-based regimens decrease breast cancer mortality by 20–30%. Anthracycline toxicities include the rare—but potential morbid—cardiotoxicity or leukemogenic effect, and the almost universal—but very distressing—alopecia. Due to potential toxicities, and large number of patients being exposed, several worldwide trials have re-examined the role of anthracycline-based regimens in the management of breast cancer. Current literature supports that anthracyclines are not required for all patients with breast cancer and should be avoided in those with high cardiac risk. Recent results from the ABC trials suggest that anthracyclines should not be spared for patients with triple negative breast cancer (regardless of axillary node involvement) or HER2−/ER+ with significant node involvement. Based on current literature, for HER2-negative patients with low-risk breast cancer, anthracyclines could be spared with regimens such as cyclophosphamide, methotrexate, and fluorouracil (CMF) or docetaxel and cyclophosphamide (TC). Patients with intermediate or high-risk breast cancer should be considered for anthracycline-based regimens based on other factors such as age, comorbidities, tumor grade, lymphovascular invasion, and genomic profiling. Patients with HER2-positive breast cancer with low risk could be treated with paclitaxel and trastuzumab. For the remaining patients with HER2 overexpression, while docetaxel, carboplatin, and trastuzumab (TCH) has demonstrated to improve disease-free survival (DFS), anthracycline-containing regimens should be discussed, especially for those with very high-risk breast cancer. Although several biomarkers, such as topoisomerase II (TOP2A) and chromosome 17 centromeric duplication (Ch17CEP) have been proposed to predict benefit from anthracycline regimens, further research is required to delineate their proper utility in the clinical setting.

Phase I Trial of Veliparib, a Poly ADP Ribose Polymerase Inhibitor, Plus Metronomic Cyclophosphamide in Metastatic HER2-negative Breast Cancer

Micro‐Abstract This a phase I study of veliparib and metronomic‐dose cyclophosphamide in patients with metastatic human epidermal growth factor receptor 2/neu negative breast cancer, an incurable disease that requires new treatment options. Our study defined the recommended phase II dose and revealed that this combination is well‐tolerated and has activity in BRCA‐mutated breast cancer. Background: Poly‐ADP‐ribose‐polymerase is an essential nuclear enzyme, involved in base‐excision repair of damaged DNA. Poly‐ADP‐ribose‐polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. Methods: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low‐dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21‐day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu‐negative breast cancer. Dose‐limiting toxicity was defined as any grade 3 non‐hematologic toxicity or grade 4 thrombocytopenia/neutropenia occurring during cycle 1. Results: A total of 31 patients were enrolled; 19 were treated with 50 mg of C and 12 were treated at higher doses (75, 100, or 125 mg), with V doses ranging from 50 to 300 mg BID. The recommended phase II dose of the combination was V 200 mg orally BID plus C 125 mg orally daily, with nausea and headache dose‐limiting at higher V dose levels. Objective response or stable disease for at least 24 weeks occurred in 3 (43%) of 7 patients with known deleterious germline BRCA mutations and 2 (11%) of 19 patients with negative/unknown mutation status (P = .1). Conclusion: The combination of oral continuous dosing of V (200 mg orally BID) with metronomic C (50, 75, 100, and 125 mg daily) is well‐tolerated and shows antitumor activity in patients with BRCA–mutation‐associated metastatic human epidermal growth factor receptor 2/neu‐negative breast cancer.

Abstract CT040: Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer

Background: Metastasis is the primary cause of death in breast cancer, yet no specific therapies are available that inhibit the metastatic process. TMEM (Tumor Microenvironment of Metastasis) are microanatomic structures formed by a Mena-expressing tumor cell, Tie2-expressing macrophage, and endothelial cell in direct content, which serve as the primary portal for tumor cell intravasation into the circulation and subsequent metastasis. High TMEM score in the primary tumor is associated with higher risk of recurrence in ER+, HER2- early breast cancer. Paclitaxel induces the formation of TMEM in the primary tumors of patients treated with neoadjuvant chemotherapy (NAC), and in the primary tumor and distant metastases in the PyMT rodent model and patient-derived xenograft (PDX) models. Intravasation of tumor cells is mediated by release of vascular endothelial growth factor (VEGF) that promotes focal vascular leakiness specifically at TMEM sites, and is derived from TMEM-associated Tie2HI/VEGFHI macrophages that release VEGF upon binding of the Tie2 receptor to angiopoietin, which is elaborated by TMEM-associated endothelial cells. The Tie2 inhibitor rebastinib inhibits intravasation at TMEM sites, reduces circulating tumor cell (CTC) burden, prevents distant metastases, and improves survival in breast cancer animal models when added to either paclitaxel or eribulin. We therefore hypothesize that the addition of a potent Tie2 inhibitor (rebastinib) to antitubulin therapy with paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC) will prevent hematogenous dissemination and distant metastasis by inhibiting TMEM function, reduce CTC burden, and improve clinical outcomes. Methods: Primary objective of this phase Ib study (NCT02824575) is to evaluate safety and tolerability of rebastinib (Tie2 inhibitor) in two dose levels (DL) (50mg or 100mg po BID) combined with paclitaxel IV 80mg/m2 (day 1, 8 and 15) or eribulin IV 1.4mg/m2 (day1 and 8) for four 21-day cycles. Key eligibility includes histologically confirmed HER2 negative MBC or not amenable to curative surgery. Up to two prior non-taxane chemotherapy regimens are allowed for rebastinib plus paclitaxel arm, while at least two chemotherapy regimens (including a taxane) are required for eribulin plus rebastinib arm. ER positive patients must have failed at least two lines of endocrine therapy including an approved CDK4/6 inhibitor. Patients require ECOG PS 0 or 1 and normal organ and marrow function. Exclusion criteria include significant ocular disease (retinal neovascularization, macular edema or macular degeneration), significant history of cardiac disease or concomitant use drugs that prolong QTc interval. Pharmacodynamic biomarkers to be measured during cycle 1(day1 and 15), cycle 2(day1 and 15) and cycle 3(day1) include CTCs, angiopoietin 1/2 levels and Tie-2 expressing monocytes. Tissue biopsy after two treatment cycles in 6 patients who have accessible tumors will be performed to evaluate TMEM score and function. With two DL of rebastinib, and 3-6 patients at each DL, it is anticipated that 6-12 patients will be required. This trial has enrolled two patients assigned to paclitaxel arm combined with rebastinib 50mg BID. Citation Format: Jesus D. Anampa, Xiaonan Xue, Maja oktay, John Condeelis, Joseph A. Sparano. Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT040. doi:10.1158/1538-7445.AM2017-CT040

Tailoring Adjuvant Therapy for Breast Cancer in the Elderly: Room for Improvement

Breast cancer is the most common cancer and leading cause of cancer death in women worldwide (1). It is a disease of aging, with a threefold higher risk for women older than 70 years compared with age 50–59 (2). Life expectancy is gradually improving in the USA and most industrialized nations, resulting in an aging of the general population, especially in women who experience longer longevity than men (3). This perfect storm of circumstances is expected to result in a tsunami of cancer affecting the elderly—a 30% increase in the overall incidence of breast cancer is expected by the year 2030, driven largely by a 57% increase in women 65 years or older (4). Although it is well known that young age is associated with increased breast cancer mortality, it is not well appreciated that breast cancer mortality may also be significantly higher in older women despite a higher incidence of more indolent estrogen receptor (ER)positive disease. For example, a recent report indicates that although the Oncotype DX recurrence score used to risk stratify ER-positive disease does not vary by age, data derived from the SEER data base indicates that older women with node-negative breast cancer and a high recurrence score had significantly higher 5-year breast cancer mortality rates compared with younger women (5). Five-year breast cancer mortality rates for those with a high recurrence score were 3%, 5%, 10%, and 22% for women age 50–59, 60–69, 70–79, and >80 years, respectively. This may be explained at least in part by less use of adjuvant chemotherapy despite a high recurrence score in older women with increasing age (74%, 67%, 56%, and 32%, respectively) (5). The implication is that more widespread use of adjuvant chemotherapy in appropriately selected patients at highest risk of recurrence could results in lower breast cancer mortality in older women. A challenge in reducing breast cancer mortality in elderly women is that age itself, and comorbidities typically associated with age, pose a “competing risk” for death (6). In addition, “chronological age” does not necessarily correlate with “functional age” and hence fitness for adjuvant systemic therapy. Although most elderly women who are candidates for adjuvant endocrine therapy associated with a low risk of acute toxicities receive it, the decision about selecting patients with high-risk disease for adjuvant cytotoxic chemotherapy commonly associated with acute toxicities is more complex. Decision aids such as Adjuvant! (www.adjuvan tonline.com) (7,8) and PREDICT (http://www.predict. nhs.uk/predict.html) (9) are widely used web-based tools that can estimate potential benefits of adjuvant therapy. Although age is integrated into both algorithms, only Adjuvant! includes an option to adjust estimates based on a comorbidity scale. Other tools such as ePrognosis (www.eprognosis.com) can provide 5and 10-year morality estimates associated with “competing risks,” which may provide additional useful information is some circumstances. In the current issue of the Breast Journal, Meresse et al. (10) carried out a population-based cohort study to evaluate adherence to adjuvant therapy guidelines according to age among French elderly women with breast cancer, and report that women (75–80 years) received chemotherapy more than four times less often than women of age 65–74. These results are concordant with other reports also indicating substantially lower adjuvant chemotherapy use in women 75 years or older (11). Meresse et al. also reported that chemotherapy rates increased in older women between 2006 and 2008 after development of oncogeriatric coordination unit that used an oncogeriatric assessment tool, which supports the potential role of such tools to tailor decisions about adjuvant chemotherapy. Address correspondence and reprint requests to: Jesus Anampa, Assistant Professor Medicine, Department of Medical Oncology. Albert Einstein College of Medicine/Montefiore Medical Center, 1695 Eastchester Rd, 2nd floor, Bronx NY 10461, USA, or e-mail: janampa@montefiore.org