Is Molecular Tailored-Therapy Changing the Paradigm for CNS Metastases in Breast Cancer?

Abstract BACKGROUND: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha < 10%. Cohort B will enroll 10 patients. The trial opened in February, 2019. NCT03765983.

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Cerebel (EGF111438): An Open Label Randomized Phase III Study Comparing the Incidence of CNS Metastases in Patients (PTS) with HER2+ Metastatic Breast Cancer (MBC), Treated with Lapatinib Plus Capecitabine (LC) Versus Trastuzumab Plus Capecitabine (TC)

Annals of Oncology ◽

10.1016/s0923-7534(20)34361-1 ◽

2012 ◽

Vol 23 ◽

pp. ixe5 ◽

Cited By ~ 12

Author(s):

X. Pivot ◽

V. Semiglazov ◽

B. Żurawski ◽

R. Allerton ◽

A. Fabi ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Metastatic Breast ◽

Phase Iii ◽

Cns Metastases ◽

Open Label ◽

Phase Iii Study

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Effect of Central Nervous System Metastases on Treatment Discontinuation and Survival in Older Women Receiving Trastuzumab for Metastatic Breast Cancer

Journal of Cancer Epidemiology ◽

10.1155/2012/819210 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Mark D. Danese ◽

Karla Lindquist ◽

Justin Doan ◽

Deepa Lalla ◽

Melissa Brammer ◽

...

Keyword(s):

Breast Cancer ◽

Central Nervous System ◽

Nervous System ◽

Metastatic Breast Cancer ◽

Proportional Hazards ◽

Metastatic Breast ◽

Cns Metastases ◽

Her2 Positive ◽

Time To Death ◽

Risk Of Death

Background. Trastuzumab improves survival in HER2-positive women with metastatic breast cancer (MBC). The consequences of longer survival include a higher likelihood of additional metastases, including those in the central nervous system (CNS). The effect of CNS metastases on both trastuzumab discontinuation and survival in older patients has not been described.Patients and Methods. We used the Surveillance Epidemiology and End Results (SEER) Medicare data to identify a cohort of 562 women age 66 or older with MBC who were diagnosed between January 1, 2000 and December 31, 2005, free of CNS metastases, and initiated trastuzumab after MBC diagnosis. Time to discontinuation and time to death were analyzed using proportional hazards models.Results. Newly diagnosed CNS metastases were associated with both higher risk of trastuzumab discontinuation (relative hazard[RH]=1.78, 95% CI 1.11–2.87) and higher risk of death (RH=2.49, 95% CI 1.84–3.37). The incidence rate of new CNS metastases was comparable among various sites of metastasis (10.7 to 14.7 per 1,000 patient-months), except for bone which was higher (24.1 per 1,000).Conclusion. The diagnosis of CNS metastases was associated with an increase in both the likelihood of discontinuing trastuzumab therapy as well as the risk of death.

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Brain metastases in breast cancer: Different survival by biological subtype and Ki67 expression

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.1069 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 1069-1069

Author(s):

D. Sartori ◽

M. Bari ◽

G. L. Pappagallo ◽

F. Rosetti ◽

S. Olsen ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Proportional Hazards ◽

Fold Increase ◽

Cox Proportional Hazards ◽

Her2 Overexpression ◽

Cns Metastases ◽

Risk Of Death ◽

Pathologic Features ◽

Increased Risk

1069 Background: Ten to 15% of patients (pts) with breast cancer will be diagnosed with central nervous system (CNS) metastases, and autopsy series suggest that up to 30% of pts have evidence of CNS disease at the time of death. The idenfication of factors that may predispose to CNS metastasis may help lead to earlier detection and possibly to improvement in disease management. Methods: Breast cancer pts with CNS metastases were identified within a database of 1300 breast cancer diganoses from 1995 to 2007 at the Department of Oncology, Azienda ULSS 13 VE. Pathologic features of tumor samples were examined using standard immunohistochemical assays. Results: Fifty-one pts with CNS metastases were identified. Median age at primary breast cancer diagnosis was 49 years (range, 28–78); median time to CNS metastases was 45 months (range, 3–244). HER2 overexpression was found in tumors from 25 pts (49.0%); 23 pts had tumors lacking overexpression of HER2, estrogen receptors (ER), and progesterone receptors (PgR) (ie, “triple negative” disease). Overexpression of p53 (at least 20% tumor cells positive), Ki67 (at least 20%), and BCL2 (at least 30%) were detected in tumors from 16 pts (31.4%), 32 pts (62.7%), and 14 pts (27.5%), respectively. Median survival from CNS involvement was 3.67 months (95% CI 2.05–5.28), with 24.4% and 15.3% of patients estimated to be alive at 12 and 24 months, respectively (Kaplan-Meier product limit method). A Cox proportional hazards analysis found that Ki67 overexpression was the only factor independently associated with a significantly increased risk of death (2.7-fold increase, p=0.028), while triple negative status was associated with a 1.8-fold increase in the risk of death (P=0.08) (Table). Conclusions: In our series of breast cancer pts with CNS metastases, nearly all had either HER2 overexpression or triple-negative disease. Pts whose tumors had higher proliferative indices, assessed by Ki67, had the poorest prognosis. [Table: see text] [Table: see text]

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Phase II study of lapatinib and tegafur combination efficacy for the treatment of HER2+ metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e11086 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e11086-e11086

Author(s):

Alexey Manikhas ◽

Ineza O. Sharvashidze ◽

Tatjana N. Kotkova

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase Ii Study ◽

Metastatic Breast ◽

Common Adverse Event ◽

Cns Metastases ◽

Previous Therapy ◽

Oral Formulations ◽

Disease Stabilization

e11086 Background: One of effective ways to overcome resistance to trastusumab is to prescribe lapatinib, an inhibitor of ErbB1 and ErbB2 receptors, in combination with capecitabine, a fluopirimidine cytostatic agent. We examined the efficacy and safety of combination of lapatinib plus tegafur, another oral fluopirimidine, in patients with ErbB2-positive metastatic breast cancer (MBC). Methods: 13 patients with HER2+ MBC were enrolled into the study. 11 patients were analyzed, as 2 women had been included into the study too late to be assessed. Median age was 43.5 years. All patients had previously received trastuzumab for MBC, 92% of patients had been treated with taxanes, 77% - with anthracyclines, and 31% received capecitabine. 69% of patients were treated with more than 2 lines of chemotherapy for MBC. The study included 4 patients with CNS metastases. During the study, the patients received lapatinib 1250 mg/day and tegafur 1200 mg/day, days 1-21, with 3-week intervals. Results: 1 patient achieved and still is in partial response which has been lasting for 5 months, while disease stabilization was observed in 9 out of 10 cases. The clinical benefit rate in this trial was 90%. There was 1 case of the disease progression. At the time of analysis median TTP was 10.1 months (95%CI 6-13). The combination of lapatinib and tegafur was effective in 4 out of 5 patients with CNS metastases. There were no adverse events greater than grade I observed on lapatinib plus tegafur therapy. Diarrhea was the most common adverse event, but it did not compromise the patients' quality of life. Conclusions: The lapatinib plus tegafur combination is a promising option for treatment of patients with HER2+ MBC after progression on trastuzumab-containing therapy. This mode was acceptable for patients who had received 2 or more lines of previous therapy. The combination was well tolerated by the patients. Both agents being oral formulations, the treatment mode is quite suitable for outpatient use.

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Outcomes of patients with HER2-negative breast cancer with central nervous system metastasis treated with capecitabine.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e11553 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e11553-e11553

Author(s):

Kadri Altundag ◽

Sercan Aksoy ◽

Mehmet Ali Nahit Sendur ◽

Emine Nilufer Guler ◽

Ibrahim Halil Gullu ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Cancer Patients ◽

Whole Brain Radiotherapy ◽

Progression Free Survival ◽

Neurological Deficits ◽

Breast Cancer Patients ◽

Cns Metastases ◽

Cns Metastasis ◽

Grade 3

e11553 Background: Systemic chemotherapy is often ineffective due to the impermeability of the blood-brain barrier (BBB) and inherent chemoresistance of CNS metastases. There are limited data supporting the use of capecitabine in this setting. The aim of this study was to evaluate the effectiveness and toxicity of capecitabine in breast cancer patients with CNS metastasis. Methods: The records of all patients with HER-2 Negative breast cancer with CNS metastasis that treated with capecitabine monotherapy were evaluated. All patients recieved capecitabine at a dose of 2,500mg/m2/day for 14 days at 3 weeks intervals. Results: Fifty-eight female patients with a median age of 42 years (min-max; 20-68) were included in this retrospective analysis. The median time to brain metastasis was 3.1 years (min-max; 0.5-15.5). Thirty (51%) patients were hormone positive, and twenty-nine (49%) were triple-negative. Forty-seven (78%) patients recieved capecitabine as first line treatment after the CNS metastasis. Only 4 patients had undergone surgery for CNS metastasis, and all patients had recieved whole brain radiotherapy before the capecitabine treatment. Five (8.5%) patents were treated with cyberknife radiosurgery. There were 6 (10%) complete (2 patient had metastasectomy for brain metastasis), and 21 (36%) partial responses with 9 (15%) patients having stable disease. Progressive disease was observed in 16 (28%) patients. 6 patients were not evaluabled for radiological evaluation. Median progression free survival time was 5 months, and median overall survival was 8.6 months. Dose reduction was required due to adverse effects in 20 patients (24%). The most frequent side effect was the hand-food syndrome (HFS), which developed in 29 patients (50%). Forty-percent of them developed grade 3 HFS disease. Diarrhea occurred in 21% of the patients, nausea in 19% of the patients. Grade 3-4 myelosupression were developed in 15% of the patients. There was no treatment-related death. Conclusions: Capecitabine is effective and well tolerated in the treatment of breast cancer patients with CNS metastases. It is feasible options HER2 negative breast cancer patients especially with neurological deficits.

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CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2014.57.1794 ◽

2015 ◽

Vol 33 (14) ◽

pp. 1564-1573 ◽

Cited By ~ 118

Author(s):

Xavier Pivot ◽

Alexey Manikhas ◽

Bogdan Żurawski ◽

Ewa Chmielowska ◽

Boguslawa Karaszewska ◽

...

Keyword(s):

Breast Cancer ◽

Epidermal Growth Factor Receptor ◽

Metastatic Breast Cancer ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Cns Metastases ◽

Human Epidermal Growth Factor ◽

Epidermal Growth

Purpose CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. Patients and Methods Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m2 per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m2 per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). Results The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, −1.6%; 95% CI, −2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. Conclusion CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.

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