Approaching Neoadjuvant Therapy in the Management of Early-Stage Breast Cancer.

Neoadjuvant therapy is integral to the treatment of early-stage breast cancer. Goals of treatment include surgical downstaging of the tumor, rendering inoperable tumors resectable, and de-escalating axillary surgery in those with clinically positive nodes. Additionally, response to treatment provides important prognostic information regarding risk of recurrence and guides future adjuvant treatment. Although chemotherapy serves as the backbone of neoadjuvant treatment, an increased understanding of the tumor\u27s clinical course as well as its molecular and genetic make-up aids in individualizing treatment and developing novel agents. This review summarizes current clinical approaches and the future direction to the management of breast cancer patients in the neoadjuvant setting

Jnk2 Effects on Tumor Development, Genetic Instability and Replicative Stress in an Oncogene-Driven Mouse Mammary Tumor Model

Oncogenes induce cell proliferation leading to replicative stress, DNA damage and genomic instability. A wide variety of cellular stresses activate c-Jun N-terminal kinase (JNK) proteins, but few studies have directly addressed the roles of JNK isoforms in tumor development. Herein, we show that jnk2 knockout mice expressing the Polyoma Middle T Antigen transgene developed mammary tumors earlier and experienced higher tumor multiplicity compared to jnk2 wildtype mice. Lack of jnk2 expression was associated with higher tumor aneuploidy and reduced DNA damage response, as marked by fewer pH2AX and 53BP1 nuclear foci. Comparative genomic hybridization further confirmed increased genomic instability in PyV MT/jnk2−/− tumors. In vitro, PyV MT/jnk2−/− cells underwent replicative stress and cell death as evidenced by lower BrdU incorporation, and sustained chromatin licensing and DNA replication factor 1 (CDT1) and p21Waf1 protein expression, and phosphorylation of Chk1 after serum stimulation, but this response was not associated with phosphorylation of p53 Ser15. Adenoviral overexpression of CDT1 led to similar differences between jnk2 wildtype and knockout cells. In normal mammary cells undergoing UV induced single stranded DNA breaks, JNK2 localized to RPA (Replication Protein A) coated strands indicating that JNK2 responds early to single stranded DNA damage and is critical for subsequent recruitment of DNA repair proteins. Together, these data support that JNK2 prevents replicative stress by coordinating cell cycle progression and DNA damage repair mechanisms

The role of JNK2 and JNK1 in breast cancer mediated invasion and metastasis

textReceptor tyrosine kinase (RTK) inhibitors are emerging as an effective therapeutic option for treatment of breast cancer patients overexpressing particular RTKs. However, more patients may benefit from an inhibitor targeting a common effector protein downstream several RTKs. The presented studies herein identify c-Jun N-Terminal Kinase 2 (JNK2), a kinase downstream multiple RTKs, as a novel target to effectively inhibit Phosphatidylinositol 3-kinase/AKT activation and metastasis. Knockdown of JNK2 in the highly metastatic 4T1.2 mammary cancer cells significantly decreased growth factor induced invasion in Boyden chambers, orthotopic tumor growth, and metastatic lesions in lungs and bone. Intra-cardiac introduction of cancer cells is utilized to specifically study the later steps in the metastatic cascade including travel of disseminated cancer cells to a secondary location. Thus, earlier steps such as the process of acquiring a malignant phenotype leading to escape from the primary tumor are bypassed. Survival was prolonged in mice receiving intra-cardiac injection of cells deficient of JNK2 either in the host or in the tumor cells, suggesting a potential role for JNK2 as a therapeutic target for advanced stage breast cancer patients. Using siRNA and inhibitors against Src and PI3K, we determined that JNK2 activity is dependent on Src and PI3K, positioning JNK2 downstream of two critical factors involved in tumor progression. Microarray analysis of JNK2 deficient tumors revealed that JNK2 positively regulates the adaptor protein Grb2 associated binding protein 2 (Gab2). Knockdown of Gab2 in 4T1.2 cells resulted in decreased tumor growth and a trend for decreased lung metastasis. In vitro, stimulation of 4T1.2 shJNK2 or 4T1.2 shGab2 cells with HGF, heregulin, or insulin resulted in impaired AKT activation, suggesting involvement of Gab2 and JNK2 in multiple RTK signaling pathways. Understanding of the intricate mechanisms involved in RTK signal transduction can contribute to drug design geared towards more effective targets, namely JNK2. The secondary goal of this research was to decipher the individual roles of JNK2 and JNK1 in metastatic breast cancer. Survival was significantly shortened in mice injected intra-cardiac with 4T1.2 shJNK1 cells. In congruence, serum Cathepsin K levels were increased and bone lesions observed were higher in mice injected with shJNK1 expressing tumor cells compared to mice injected with control cells. In sharp contrast, jnk1-/- mice displayed dramatically increased survival and fewer bone lesions upon intra-cardiac injections of 4T1.2 cells. Collectively, these data suggest cell and isoform specific roles for JNKs.Pharmac

Neratinib: the emergence of a new player in the management of HER2+ breast cancer brain metastasis

HER2-positive (HER2+) breast cancer has become an effectively treatable disease in the era of targeted therapies, and outcomes have improved such that prognosis of this subtype is demonstrated to be superior to HER2-negative disease. Despite these advances, durable responses in HER2+ metastatic disease are challenged by the increased risk for brain metastasis. Neratinib is an irreversible pan-HER kinase inhibitor that has emerged as an effective agent when combined with capecitabine for the management of HER2+ metastatic breast cancer patients with brain metastasis. The randomized, Phase III, NALA trial compares neratinib plus capecitabine to a currently prevailing regimen of lapatinib plus capecitabine and is provided herein. Analysis of NALA portends meaningful changes on the horizon for the management of HER2+ metastatic breast cancer. </jats:p

Abstract P5-14-18: Socioeconomic and geographic barriers affect rates of standard of care therapy utilization in patients with hormone receptor positive, HER2 negative metastatic breast cancer

Abstract Background: It is of value to determine whether treatment disparities exist in the management of hormone receptor positive (HR+), HER2 negative (HER2-) MBC due to location, age, gender, practice type, or payment methods. The objective of this study was to evaluate prescription patterns for CDK46 inhibitors (CDKI) in the first line setting in patients with HR+ HER2- MBC at the University of Pittsburgh Medical Center (UPMC), a tertiary care academic center with a large satellite clinic network. Methods: Data were obtained using a quality care insight tool (QCIT, Pfizer) which provided information regarding MBC treatment utilization patterns using the pharmacy and medical claims data from the IQVIA Anonymized Patient Longitudinal Dataset. This data set includes HIPAA-compliant anonymized information on diagnostic codes, tests, prescribed treatments, and procedures for 17.9 million US cancer patients from 2012 onward. Analysis was focused on a comparison of a UPMC patient cohort to a national cohort of patients with HR+/HER2- MBC to better understand local prescription patterns. Inferential statistical analysis was not applicable to data obtained from the QCIT tool and thus was not performed. Inclusion criteria included (1) patients ≥ 18 years of age on first breast cancer occurrence; (2) medical claim indicating HR+ breast cancer and the absence of HER2 positivity; and/or (3) a pharmacy claim for a CDKI; and (4) at least one medical or pharmacy claim six months before and six months after MBC diagnosis and CDKI prescription. Results: Comparison of national treatment prescription patterns to treatments utilized at UPMC facilities for patients with HR+ HER2- MBC in the first-line setting demonstrated higher rates of CDKI-based therapy utilization within UPMC institutions comparatively (61% vs. 54%, respectively). Rates of chemotherapy use in the UPMC population were concordantly lower than the national average (1% vs. 5%). The rate of CDKI-based therapy utilization in MBC patients in the first line was higher at urban UPMC sites vs. their rural counterparts (82% vs. 70%). Patients with Medicare showed notably lower CDKI utilization rates compared to their counterparts receiving Medicaid (43% vs 83%) or commercial third-party insurance (43% vs. 63%). Conclusions: Higher rates of CDKI utilization in the first-line metastatic setting indicate more widespread adoption of first line CDKI at UPMC (a tertiary health care system with a large community satellite network) as compared to national averages. Within the UPMC patient population, lower rates of first line CDKI utilization in patients receiving Medicare or in rural areas may be reflective of socioeconomic obstacles, which limit patient access to care. Further research is planned to investigate possible clinical or social determinants of these differences. Citation Format: Christopher DeHaven, Azadeh Nasrazadani, Adam Brufsky. Socioeconomic and geographic barriers affect rates of standard of care therapy utilization in patients with hormone receptor positive, HER2 negative metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-14-18.</jats:p

c-Jun N-terminal Kinase 2 Regulates Multiple Receptor Tyrosine Kinase Pathways in Mouse Mammary Tumor Growth and Metastasis

c-Jun N-terminal kinase 2 (JNK2) isoforms are transcribed from the jnk2 gene and are highly homologous with jnk1 and jnk3 transcriptional products. JNK proteins mediate cell proliferation, stress response, and migration when activated by a variety of stimuli, including receptor tyrosine kinases (RTKs), but their ability to influence tumor metastasis is ill defined. To evaluate JNK2 in this manner, we used the highly metastatic 4T1.2 mammary tumor cells. Short hairpin RNA expression directed toward JNK2 (shJNK2) decreases tumor cell invasion. In vivo, shJNK2 expression slows tumor growth and inhibits lung metastasis. Subsequent analysis of tumors showed that shJNK2 tumors express lower GRB2-associated binding protein 2 (GAB2). In vitro, knockdown of JNK2 or GAB2 inhibits Akt activation by hepatocyte growth factor (HGF), insulin, and heregulin-1, while phosphorylation of ERK is constitutive and Src dependent. Knockdown of GAB2 phenocopies knockdown of JNK2 in vivo by reducing tumor growth and metastasis, supporting that JNK2 mediates tumor progression by regulating GAB2. The influence of jnk2 in the host or microenvironment was also evaluated using syngeneic jnk2–/– and jnk2+/+ mice. Jnk2–/– mice experience longer survival and less bone and lung metastasis compared to jnk2+/+ mice after intracardiac injection of 4T1.2 cells. GAB2 has previously been shown to mediate osteoclast differentiation, and osteoclasts are critical mediators of tumor-related osteolysis. Thus, studies focusing on the role of JNK2 on osteoclast differentiation were undertaken. ShJNK2 expression impairs osteoclast differentiation, independently of GAB2. Further, shJNK2 4T1.2 cells express less RANKL, a stimulant of osteoclast differentiation. Together, our data support that JNK2 conveys Src/phosphotidylinositol 3-kinase (PI3K) signals important for tumor growth and metastasis by enhancing GAB2 expression. In osteoclast progenitor cells, JNK2 promotes differentiation, which may contribute to the progression of bone metastasis. These studies identify JNK2 as a tumor and host target to inhibit breast cancer growth and metastasis