ASCO guidelines in HER2+ BCBM - Open questions/next steps, Conclusions.

HER2-positive breast cancer brain metastasis: A new and exciting landscape
REVIEW - 2 July 2020. - WILEY online library.

ASCO guidelines in HER2+ BCBM - Open questions/next steps, Conclusions.

4| RECOMMENDATIONS

4.1| ASCO guidelines in HER2+ BCBM
The American Society of Clinical Oncology (ASCO) has published periodic and timely guidelines for management of BrM in patients withHER2+ advanced BC. Those guidelines are expert consensus-based recommendations following a targeted, systematic literature review.The most recent guideline was published in 2018 and had similar recommendations to the previous version, published in 2014.115In summary, cases with favorable prognosis and single or limited 2-4BrM should receive some combination of surgery and radiation, depending on size, resectability and symptoms. When presenting with diffuse BrM, patients should receive WBRT, and if poor clinical prognosis, palliative care is indicated. If progression of CNS disease following initial radiation therapy occurs, some form of local therapy with radiation and/or surgery should be considered when possible, as well as a clinical trial or best supportive care. Systemic therapy should not be switched if systemic extracranial disease is not progressing. Traditional HER2-targeted therapy algorithms for HER2+ metastatic BC should be offered when systemic disease is progressive. A suggested algorithm for multidisciplinary management of care for patients with HER2+ BCBrM is presented in Figure 1.

4.2| Open questions/next steps
Many questions remain to be answered in the management of HER2+ BCBrM around drug delivery, subtype discordance, and the unique biology of BrM. Obtaining active and homogeneous drug penetration into CNS metastatic lesions is only one obstacle to overcome. To complicate matters, discordance between BC subtype markers have also been demonstrated when BrM are compared to primary tumors.35,116 Further-more, whole-exome sequencing of patient-matched BrM and primary tumors demonstrate that metastatic lesions are a product of branched evolution, with mutations“private to the BrM.”117 Based on those findings and paving the way of precision medicine strategies into BrM management, a phase II clinical trial proposing genomically-guided treatment in BrM was developed (NCT03994796). Patients with histologically proven BrM from any solid tumor, including HER2+ BC, are eligible and will be treated based on specific actionable mutations inherent to the BrM. Patients will be matched to brain permeable therapies based on alterations found in their BrM: CDK alterations to abemaciclib, mTOR/AKT/PI3K alterations to the dual mTOR/PI3K inhibitor, paxalisib/GDC-0084, and NTRK/ROS1 fusions (lung BrM only) to entrectinib. The primary endpoint of this novel clinical trial is overall CNS response rate..
Considering the issues of drug penetration in the CNS and the biologic cascade promoting BrM, preclinical data using a mouse xeno-graft model of BCBrM demonstrates that temozolomide administered in a preventive fashion can prevent the development of BrM. In these models, temozolomide did not result in reduction in established BrM.118Based on this observation, a phase I/II clinical trial for secondary prevention of BrM in HER2+ BC has been developed, enrolling patients after an initial local therapy to receive T-DM1 with or with-out temozolomide, with the goal to prevent and decrease incidence of new BrM.119This represents a new study design of“secondary prevention”in BrM clinical trials which could also be utilized in the development of clinical protocols for other subtypes of BCBrM.As immunotherapy has emerged as one of the most promising ways to approach cancer therapy over the last decade, HER2+ and TNBC are known to be the most immunogenic subtypes of BC. Biomarkers correlated with immunogenicity such as tumor-infiltrating lymphocytes (TIL) levels, PD-L1 expression and tumor mutational burden (TMB) are reportedly more frequent in the HER2+relative to the luminal subtypes of BC.120-122This observation has led to the development of immunotherapy strategies and clinical trials of immunotherapy for advanced HER2+ BC. Though preliminary clinical evidence has shown modest activity of immune checkpoint inhibitors in metastatic HER2+ BC, new strategies and combinations targeting BrM are under evaluation (Table 2). One interesting approach is the use of chimeric antigen receptor-engineered T cells (CART) to targetHER2+ BCBrM, demonstrated to be effective with intraventricular delivery of HER2-CAR constructs in xenograft models 68 and currently being investigated in clinical trials (Table 2).

5| CONCLUSIONS
BrM are a frequent clinical challenge for patients with advanced HER2+breast cancer. The continuous development of newer, brain permeable,anti-HER2 therapeutic options has steadily improved the impact of systemic therapy for patients with metastatic HER2+ breast cancer. In parallel, there has been an increased awareness of BrM as a clinically unmet need for this subtype of breast cancer. The complexity of CNS biology and the unique local microenvironment coupled with the historically limited availability of clinical trials for patients with CNS involvement has contributed to a poorer prognosis for this population in the past. This picture is slowly and steadily changing, in large part due to a paradigm shift resulting in the inclusion of patients with BrM in large,randomized, phase 3 clinical trials such as HER2Climb. Enrollment of patients with BrM in future clinical trials evaluating promising, brain permeable, HER2-targeted therapies should be at the forefront to maintain this forward momentum, with the goal of continuing to improve our patients’ survival and quality of life in a meaningful way.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cnr2.1274

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