Front Row Seat: The Enigma of the Blood-Brain Barrier & More with Dr. Nancy Lin
Live from Stage 4 | Episode # 024| 4/14/2026 | Front Row Seat
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Guest
Nancy U. Lin, MD
A renowned medical oncologist based in Boston, MA.. She specializes in all stages of breast cancer, with a globally recognized focus on metastatic breast cancer and brain metastases.
Current Roles & Affiliations
Dana-Farber Cancer Institute: Associate Chief of the Division of Breast Oncology at the Susan F. Smith Center for Women's Cancers.
Harvard Medical School: Professor of Medicine.
Leadership: Founder and Director of the Metastatic Breast Cancer Program and the Program for Patients with Breast Cancer Brain Metastases.
Research: Principal Investigator for the Translational Breast Cancer Research Consortium at Dana-Farber.
Research & Clinical Expertise
Dr. Lin's career is defined by her efforts to develop effective systemic therapies for cancers that have spread to the brain—a traditionally difficult-to-treat complication due to the blood-brain barrier.
HER2-Positive Breast Cancer: She has led multiple clinical trials, including the landmark HER2CLIMB study, which evaluated tucatinib for patients with brain metastases.
Innovative Trials: Her research explores novel diagnostic methods, targeted therapies, and mechanisms of resistance to HER2-based treatments.
Global Guidelines: She holds leadership roles in international committees, such as the Response Assessment in Neuro-Oncology (RANO) working group, to establish standards for managing metastatic disease.
Education & Training
Medical Degree: Graduated cum laude from Harvard Medical School in 1999.
Residency: Internal Medicine at Brigham and Women’s Hospital.
Fellowships: Hematology and Medical Oncology at Dana-Farber Cancer Institute.
Notable Awards
Distinguished Researcher Award (2023).
Women in Oncology Award (2023).
George Canellos Award for Excellence in Clinical Investigation (2011).
Young Investigator Award from Conquer Cancer (2005
Summary
In this episode, Victoria Goldberg sits down with Dr. Nancy Lin, medical oncologist at Dana-Farber Cancer Institute and a leading expert in metastatic breast cancer brain metastasis, to explore one of the most complex and rapidly evolving areas in breast cancer treatment.
Dr. Lin opens with an overview of the current treatment landscape for brain metastasis across all subtypes. For HER2-positive patients, she discusses antibody drug conjugates like T-DXd and TDM-1, the oral TKI tucatinib, and how focused radiation — including SRS, Gamma Knife, and CyberKnife — is now preferred over whole-brain radiation for most patients. For ER-positive and triple-negative patients, she highlights emerging data on CDK inhibitors and ADCs showing real activity in the brain.
Dr. Lin then offers a candid assessment of the HER2 CLIMB-05 trial — why the brain metastasis prevention data fell short of expectations — and shares intriguing findings from the Patina trial suggesting that palbociclib (Ibrance) may reduce brain metastasis incidence in ER+/HER2+ patients.
The conversation then turns to the central theme of Dr. Lin's presentation at the ABC8 Global Advanced Breast Cancer Conference in Lisbon: the enigma of the blood-brain barrier. She explains the critical distinction between the intact blood-brain barrier and the disrupted blood-tumor barrier — and why that difference has fundamentally changed how oncologists think about treating brain metastasis. Many drugs once dismissed as "unable to cross the BBB" are proving effective in brain mets precisely because the blood-tumor barrier is leakier than the healthy barrier.
Dr. Lin also previews what's coming next: focused ultrasound with microbubbles to temporarily open the blood-brain barrier, receptor-mediated transcytosis to ferry drugs directly into the brain, and a new generation of drugs — including ZN-1041 (zilanertinib), IAMBIC's HER2-targeted compound, and brain-penetrant PARP inhibitors — designed from the ground up to cross the blood-brain barrier.
The episode closes with a discussion on routine brain MRI screening — an area where clinical thinking is shifting — and a look at Dr. Lin's current research, including a trial of Dato-DXd for ER+ and triple-negative brain metastasis and a registry for leptomeningeal disease (LMD), which will be the focus of a dedicated future episode.
Key topics covered:
Current treatments for HER2+, ER+, and triple-negative brain metastasis
Tucatinib and the HER2 CLIMB-05 prevention data
Palbociclib and brain metastasis incidence from the Patina trial
The blood-brain barrier vs. the blood-tumor barrier
Focused radiation: SRS, Gamma Knife, CyberKnife, and proton CSI for leptomeningeal disease
Focused ultrasound, microbubbles, and the Trojan horse approach to drug delivery
New drugs designed specifically for brain penetration
Routine brain MRI screening: where the evidence is heading
Preview: leptomeningeal disease and the LMD registry
This episode is for informational purposes only and does not constitute medical advice. Visit livefromstage4.org for transcripts, resources, and additional information on topics discussed.Key Takeaways
Key Takeaways
Treatment options for brain mets have expanded significantly. Across all subtypes — HER2+, ER+, and triple negative — there are now more effective options than ever, including ADCs, oral TKIs like tucatinib, and precision radiation techniques.
Tucatinib treats brain mets but hasn't proven to prevent them. The HER2 CLIMB-05 trial showed tucatinib helps patients who already have brain metastasis, but did not show a convincing signal for preventing brain mets in patients who didn't yet have them.
Palbociclib (Ibrance) may help prevent brain metastasis in ER+/HER2+ patients. A subanalysis of the Patina trial found fewer brain metastasis diagnoses in patients on the palbociclib arm — a meaningful and lasting effect, though not from a perfectly designed screening study.
The blood-tumor barrier is not the same as the blood-brain barrier. When cancer spreads to the brain, it disrupts the barrier, making it leakier. Many drugs once thought unable to reach the brain — including ADCs — actually do get into brain metastases effectively enough to produce responses.
Focused radiation is now preferred over whole-brain radiation for most patients. SRS, Gamma Knife, and CyberKnife allow precise targeting of individual tumors. Whole-brain radiation is increasingly reserved as a later option.
Proton CSI is a game-changer for leptomeningeal disease. It delivers radiation to the entire brain and spinal cord with far less toxicity to surrounding organs, making treatment accessible to patients who previously weren't candidates.
Treatment decisions are always personalized. Choosing between radiation and systemic therapy depends on subtype, number of lesions, location, prior treatment history, and patient preference — always a collaborative decision.
New drugs are being designed specifically to cross the blood-brain barrier. This is a shift from the past, when brain penetration was an afterthought. Compounds like zilanertinib (ZN-1041) and brain-penetrant PARP inhibitors are in early trials with promising results.
Focused ultrasound with microbubbles can temporarily open the blood-brain barrier. This experimental approach allows drugs to enter the brain at higher concentrations, then lets the barrier reseal naturally — already showing early results in glioblastoma patients.
Brain metastasis subtype can differ from the original tumor. About 15% of tumors that were HER2-negative elsewhere can be HER2-positive in the brain. If surgery is performed, always request full receptor testing (ER, PR, HER2) on the brain tissue.
Routine brain MRI screening guidelines are likely to change. Evidence is building, and Dr. Lin expects a significant shift in recommendations within the next two years as new trial data emerges.
Leptomeningeal disease (LMD) is a separate and serious complication that requires its own treatment approach and will be covered in a dedicated future episode.
Ongoing/Active Clinical Trials:
ELECTRA –Elacestrant (Orserdu) in combination with abemaciclib (Verzenio) demonstrated clinical activity and was well tolerated in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer who received prior treatment with endocrine therapy and another CDK4/6 inhibitor, according to data from the phase 1b/2 ELECTRA trial (NCT05386108) presented at the 2024 ESMO Congress
DATO-Base: A phase II study of DATOpotamab deruxtecan for patients with breast cancer brain metastases or leptomeningeal disease
ZN-1041 (now "Zongertinib" / "tib") As of 2025, preliminary data suggested ZN-1041 is a "best-in-class" BBB-penetrable HER2 inhibitor. Early trials (NCT04487236) showed encouraging results, including a 79.4% confirmed response rate and 100% disease control rate in some cohorts. Studies show promise for ZN-1041 combined with trastuzumab deruxtecan (T-DXd) and capecitabine.
Iambic Therapeutics IAM1363-01: A phase 1/1b study of a selective and brain-penetrant HER2 inhibitor for HER2-driven solid tumors
LMD Registry – Not a trial per se, but a registry run by Dr. Lin and Dr. Satah Sammons for leptomeningeal disease patients, with potential collaboration with European colleagues.
Completed/Referenced Studies:
HER2-CLIMB – Original trial testing Tucatinib + Trastuzumab + Capecitabine in HER2+ metastatic breast cancer (later-line). First to include patients with active, untreated brain mets. Showed ~doubling of CNS progression-free survival and improved overall survival. Changed standard of care.
HER2-CLIMB-05 – Follow-up trial testing whether Tucatinib could prevent brain metastases in first-line HER2+ patients on maintenance therapy. Overall positive for disease control (especially in ER-, HER2+ subtype, delaying chemotherapy by ~1 year), but disappointing on CNS prevention signal.
PATINA trial – Maintenance trial for ER+/HER2+ patients. Adding Palbociclib (Ibrance) to Herceptin + Perjeta + hormonal therapy showed ~4 years of tumor control. A sub-analysis showed fewer brain metastasis diagnoses in the Palbociclib arm, sustained over 3 years.
Studies Referenced in Passing (Focused Ultrasound):
Pilot/non-randomized studies in glioblastoma (GBM) using focused ultrasound + microbubbles to temporarily open the blood-brain barrier — patients survived longer than typical GBM expectation.
