Cancer Central Nervous System Metastases Research Articles

NCMP-16. CNS METASTATIC PATTERNS IN BREAST CANCER TREATED WITH CDK4/6 INHIBITORS: PRELIMINARY RESULTS OF A RETROSPECTIVE ANALYSIS

Abstract BACKGROUND CDK4/6 inhibitors combined with hormonal therapy or as monotherapy (abemaciclib) play an important role in the management of hormone receptor positive, HER-2 negative breast cancer (BC). To date, these drugs were shown to improve progression-free survival, whereas their comparative effect modulating breast cancer central nervous system metastases (CNSm) has not yet been extensively studied. Here, we present the early findings and analytic plan of our retrospective study to evaluate CNSm patterns and differences among CDK4/6-inhibitors in BC. METHODS In this retrospective chart review study, we queried the Johns Hopkins Electronic Medical Record from 1/1/2014 to 4/25/2024 using the following prescreening criteria: 1) Age ≥18 years; 2) Diagnosis and/or problem list including BC; 3) Palbociclib, abemaciclib, or ribociclib included in the medication list. The identified patients were dichotomized based on the presence/absence of ICD10 codes for CNSm and are currently being chart-reviewed. Patients without longitudinal data or confirmed CNS or with CNSm diagnosed before/within 1 month of CDK-inhibitor initiation were excluded. Population: Prescreening identified 1,419 patients (1,055 palbociclib, 301 abemaciclib, 145 ribociclib) of whom 239, 36, and 19 patients had ICD10 codes for brain metastases, respectively. After exclusion of false positives from this cohort, we confirmed 53 patients with CNSm in the palbociclib, 3 in the ribociclib, and 1 in the abemaciclib group. RESULTS We present the current data from the first-line palbociclib cohort (N=53) where, median time to CNSm on was 24 months (interquartile range 13-46). Fifty-two (98.1%) patients had documented bone, 31 (58.5%) dural, 7 (13.2%) leptomeningeal, and 33 (62.3%) calvarial involvement. Dural and calvarial metastases were strongly associated with each other (pearson-chi2=10.7; p=0.001). CONCLUSIONS This is a work-in-progress, with early preliminary findings showing a high rate of dural and calvarial metastases in this cohort. A more detailed review of the dataset that will also include the CNS-metastasis-free cohort is underway.

“Triple-Negative Breast Cancer Central Nervous System Metastases From the Laboratory to the Clinic”

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers and has an incidence as high as 50% of brain metastases once patients develop advanced disease. The lack of targeted and effective therapies, characteristic of this subtype of breast cancer, is especially evident once central nervous system (CNS) metastases occur. Compared with other subtypes of breast cancer, TNBC patients have the shorter interval from diagnosis to development of brain metastases and the shorter overall survival once they occur, a median of 4 to 6 months. Preclinical studies of TNBC and CNS microenvironment are actively ongoing, clarifying mechanisms and orienting more effective approaches to therapy. While the first drugs have been specifically approved for use in metastatic TNBC, data on their CNS effect are still awaited.

Review: Brain Metastases in Bladder Cancer

Nearly 50% of bladder cancer patients either present with metastatic disease or relapse distantly following initial local therapy. Prior to platinum-based chemotherapy, the incidence of bladder cancer central nervous system metastases was approximately 1%; however, their incidence has increased to 3–16% following definitive treatment as platinum-based regimens have changed the natural history of the disease. Bladder cancer brain metastases are generally managed similarly to those from more common malignancies such as non-small cell lung cancer, with surgery +/–adjuvant radiotherapy, or radiotherapy alone using stereotactic radiosurgery or whole brain radiotherapy. Limited data suggest that patients with inoperable urothelial carcinoma brain metastases who are not candidates for stereotactic radiosurgery may benefit from shorter whole brain radiation therapy courses compared to other histologies, but data is hypothesis-generating. Given improvements in the efficacy of systemic therapy and supportive care strategies for metastatic urothelial carcinoma translating in improved survival, the incidence of intracranial failures may increase. Immune checkpoint blockade therapy may benefit cisplatin-ineligible metastatic urothelial carcinoma patients as first-line therapy; however, the effectiveness of immune checkpoint blockade to treat central nervous system disease has not been established. In this review, we discuss the incidence and management of bladder cancer brain metastases and considerations regarding variations in management relative to more commonly encountered non-urothelial histologies.

Etoposide and temozolomide in combination for the treatment of progressive small-cell lung cancer central nervous system metastases: two cases.

Progression of central nervous system (CNS) metastases from small cell lung cancer (SCLC) after radiation therapy is associated with a poor prognosis. We present two cases of patients with progressive CNS metastases from SCLC treated with oral temozolomide and etoposide. Sustained clinical responses and radiographic stability were demonstrated. The palliative chemotherapy regimen was well tolerated. A regimen of oral temozolomide and etoposide for progressive CNS metastases from SCLC is well tolerated and may be associated with sustained stability of disease.

T-DM1 to induce response in central nervous system (CNS) metastases from Her2 +ve metastatic breast cancer (MBC).

582Background: Radiotherapy (RT) remains the mainstay of treatment for breast cancer CNS metastases although responses to systemic therapy are seen. TDM1 is a novel antibody-drug conjugate of trastuzumab and the cytotoxic emtansine. The response rate of breast cancer CNS metastases to TDM1 was assessed retrospectively. Methods: Case notes were reviewed for all patients treated with T-DM1 for a diagnosis of HER2+ MBC treated at a single institution between 1/2/2010 and 1/12/2015. The proportion with CNS metastases progressing at commencement of TDM1 was determined to assess the activity of TDM1 in active CNS disease. Results: A total of 76 patients were identified with a median age of 56 years (range 32-81). TDM1 was given as 1st line in 7, 2nd line in 36, 3rd line in 8 and 4th or greater in 24.Patients received a median of 7 cycles of TDM1 (range 1-70) and were followed up for median of 460 days (range 29-2017days). CNS metastases were present in 23 of 76 patients at commencement of TDM1 and were actively...

Abstract P4-14-19: ONT-380 in the treatment of HER2+ breast cancer central nervous system (CNS) metastases (mets)

Abstract Background: The risk of CNS involvement in patients with HER2+ metastatic breast cancer (MBC) is high. The natural history of HER2+ CNS metastases (mets) is different from other breast cancer subtypes; there is a longer time from metastatic diagnosis to CNS relapse, greater control of extracranial disease at the time of CNS relapse, and longer median overall survival from the time of CNS relapse. Local treatments, i.e., surgery and/or radiation, remain the mainstay of treatment for HER2+ CNS disease as standard systemic therapy options have limited efficacy. ONT-380, a potent HER2 selective tyrosine kinase inhibitor with minimal EGFR-like side effects, has been associated with increased survival compared to lapatinib or neratinib in an animal model of HER2+ CNS disease. Here, we describe 24 pts from two studies with response-evaluable CNS mets treated with ONT-380 in combination with other systemic therapies. Methods: Pts with asymptomatic untreated or post-treatment progressive CNS mets were enrolled in ongoing phase 1b studies of ONT-380 + ado-trastuzumab emtansine (T-DM1) or ONT-380 ± trastuzumab (T) ±capecitabine (C). All pts received treatment in 21 day cycles including ONT-380 300 mg PO BID and approved doses of either T-DM1, T or C alone, or T+C. Eligibility criteria for all pts included prior treatment with T and a taxane, and for pts receiving T and/or C, prior T-DM1. Prior lapatinib was allowed. Assessments included safety, systemic tumor response per RECIST 1.1, and CNS tumor response by MRI every 2 cycles per modified RECIST 1.1. Results: 24 pts (10 with untreated CNS mets and 14 with progressive CNS mets after local therapy) received ONT-380 plus T-DM1 (n =14), C (n=1), T (n = 5) or T+C (n = 4) for 1-8 cycles. Of these 24 pts, 14 are evaluable for response in the CNS (at least one follow-up MRI); 7 pts have not yet been rescanned, and 3 are non-evaluable. In the 14 response-evaluable pts, best CNS response has been: 1 CNS CR (T-DM1), 4 CNS PR (T-DM1 n = 2; T+C n = 1; C n=1) and 9 CNS SD (T-DM1 n = 5; T n = 3; T+C n=1). Pts with CR or PR (prior lapatinib n=2; prior pertuzumab n=2; prior T-DM1 n=2) all had > 50% decrease in CNS target lesions. One CNS non-evaluable pt (T) had a 15% increase in their target lesion and underwent surgical resection; pathology, however, revealed no viable tumor with only necrotic tissue present. Two additional CNS non-evaluable pts (T-DM1 n=1; C+T n=1) were taken off study due to systemic PD after treatment was held for AEs (Gr 3 AST/ALT elevation [n=1]; Gr 4 edema in thalamic lesion [n=1]). No other ≥ Gr 3 ONT-380 related events were reported. Systemic disease control was also seen, with a best response in 17 evaluable pts of 6 PR, 9 SD, and 2 PD. Conclusions: This case series demonstrates early clinical signs of activity of ONT-380 against HER2+ CNS mets in combination with other systemic agents. Further study of the CNS activity of ONT-380 is ongoing and further studies are being planned. Updated results will be reported. Clinical trial information: NCT01983501, NCT02025192. Citation Format: Murthy RK, Hamilton E, Borges VF, Moulder S, Aucoin N, Welch S, Chaves J, Falkson CI, Walker L, Ferrario C. ONT-380 in the treatment of HER2+ breast cancer central nervous system (CNS) metastases (mets). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-19.

Etoposide and Temozolomide in Combination for the Treatment of Progressive Small-Cell Lung Cancer Central Nervous System Metastases: Two Cases

Progression of central nervous system (CNS) metastases from small cell lung cancer (SCLC) after radiation therapy is associated with a poor prognosis. We present two cases of patients with progressive CNS metastases from SCLC treated with oral temozolomide and etoposide. Sustained clinical responses and radiographic stability were demonstrated. The palliative chemotherapy regimen was well tolerated. A regimen of oral temozolomide and etoposide for progressive CNS metastases from SCLC is well tolerated and may be associated with sustained stability of disease.