Front Row: SABCS 2025 Insights with Dr. Francisco Esteva

Live from Stage 4 | Episode # 011| 1/13/2026 | Front Row

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Guest

Francisco J. Esteva, MD, PhD

Dr. Esteva is a board-certified medical oncologist specializing in breast cancer with over 35 years of experience. He is currently the Chief of the Division of Hematology and Medical Oncology at Lenox Hill Hospital and a Professor of Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.

Professional Roles and Leadership

• Northwell Health: At Northwell Health Cancer Institute, he also serves as the Director of Breast Cancer Translational Research.

• Previous Experience: Before joining Northwell in 2021, he held positions at NYU Langone Health, The University of Texas MD Anderson Cancer Center, and Cellectis. 

Research and Clinical Expertise

• Breast Cancer Specialization: Dr. Esteva focuses on treating various breast cancer subtypes.

• Drug Development: He has contributed to the development of therapies like trastuzumab (Herceptin), pertuzumab, and lapatinib.

• Clinical Trials: He has been involved in over 100 clinical trials and authored numerous peer-reviewed articles and book chapters.

• Molecular Research: His research includes studying resistance to HER2-targeted therapies and developing multi-gene assays. 

Education and Training

• Medical Degree & PhD: University of Zaragoza School of Medicine, Spain.

• Residency: Internal Medicine at Cooper University Hospital.

• Fellowship: Medical Oncology at Georgetown University Medical Center. 

Honors and Memberships

• Awards: He received the Susan G. Komen Greater NYC "Physician of Impact Award" in 2019.

• Memberships: He is an elected member of the American Society for Clinical Investigation (ASCI) and a Fellow of the American College of Physicians (ACP).

• Public Education: He has a YouTube channel called "Cancer Treatment Updates" to help explain oncology topics. 

Detailed Summary

Victoria Goldberg opens the first episode of 2026 and the first episode of the science-centered Front Row series, with optimism about the groundbreaking advances in breast cancer treatment. She introduces Dr. Francisco Esteva, whom she met on a plane returning from the San Antonio Breast Cancer Symposium, and invited him to discuss the latest metastatic breast cancer findings.

Dr. Esteva describes the San Antonio Breast Cancer Symposium as the premier breast cancer symposium in the world, showcasing the latest advancements in both early-stage and metastatic disease.

HER2-Positive Metastatic Breast Cancer

DESTINY-BREAST09: New First-Line Standard

Clinical Implications:

• Will become Dr. Esteva's next first-line treatment for HER2+ metastatic disease

• Represents a major leap from the CLEOPATRA regimen (which showed significant improvement when pertuzumab was added to trastuzumab and taxane)

• 40 months PFS on first-line therapy is remarkable compared to historical two-year overall survival when Dr. Esteva was a fellow

Important Considerations:

• Treatment personalization remains crucial

• Not all patients may tolerate treatment until progression

• Alternative approach: Give limited cycles of Enhertu (e.g., 6 cycles), then switch to trastuzumab-pertuzumab maintenance for patients with good response and lower disease burden

• Patients in clinical trials are highly selected "cancer Olympians" - real-world patients may have comorbidities requiring adjusted approaches

HER2CLIMB-05: Tukatinib for Brain Metastasis Prevention

Study Design:

• Added tukatinib (selective HER2 tyrosine kinase inhibitor) to trastuzumab-pertuzumab maintenance after THP induction

Results:

• ER-negative patients: 44% reduction in risk of progression or death, with 12-month improvement in PFS

• ER-positive patients: 27% reduction in risk of progression or death, with 7-month improvement in PFS

• Effective in preventing brain metastases

Clinical Significance:

• Tukatinib is more selective than older TKIs like lapatinib (which also blocks EGFR) and neratinib

• Addresses the biggest fear for HER2+ patients: developing brain metastases

• Raises questions about screening asymptomatic patients with brain MRI

Screening Discussion:

• Current standard: MRI only with neurological symptoms

• Some experts propose screening high-risk patients (extensive visceral disease, aggressive tempo)

• Dr. Esteva's approach: Would do baseline MRI for newly diagnosed metastatic HER2+ patients, then only repeat if symptoms develop or if using tukatinib anyway

PATINA Trial: Adding CDK4/6 Inhibitors

• Added palbociclib to CLEOPATRA maintenance regimen for ER+/HER2+ patients

• Showed significant improvement

• Represents evolution beyond pure CLEOPATRA protocol

Historical Context:

• CLEOPATRA study had unusual design: ER-positive patients didn't receive mandatory hormone therapy

• Modern practice includes tamoxifen or aromatase inhibitor for ER-positive disease

• PATINA adds both hormone therapy AND CDK4/6 inhibitor to CLEOPATRA

Triple-Positive Disease Recognition

Victoria notes an important shift: triple-positive disease (ER+/HER2+) is now recognized as its own subtype rather than being grouped with HER2+/ER- disease. This provides more treatment options, including addressing PIK3CA mutations (present in ~30% of HER2+ patients) that currently have limited targeted therapy options in the HER2+ space.

PI3K Pathway Discussion

Dr. Esteva shares his extensive research history in this area:

• Published first paper in Cancer Cell (2004) showing PTEN loss associated with Herceptin resistance

• PTEN is a tumor suppressor gene regulating the PI3K/AKT/mTOR pathway

• Published study combining trastuzumab with everolimus (mTOR inhibitor) in Journal of Clinical Oncology

• Newer agents like capivasertib (AKT inhibitor) offer better safety profiles than alpelisib (PI3K inhibitor with significant glucose metabolism toxicity)

• Challenge: These agents are primarily studied in ER+/HER2- disease, and insurance may not approve for HER2+ patients despite biological rationale

Treatment Sequencing Challenges

Victoria raises critical question: What happens after progression on antibody drug conjugates (ADCs)?

• Lines 3, 4, and beyond are unclear

• Poster at San Antonio by Sarah Tolaney's group at Dana-Farber showed subsequent treatments after ADCs are not very effective

• Much to discover in this space

Hormone Receptor-Positive (ER+/HER2-) Metastatic Breast Cancer

Oral SERDs: The New Frontier

Current Landscape:

• Imlunestrant: Recently FDA-approved (2025) as monotherapy for ESR1-mutated disease

• Elacestrant: Also approved for ESR1-mutated disease

• Camizestrant: Presented at ASCO with SERENA-6 trial

Dr. Esteva's Current Approach

First-Line:

• Aromatase inhibitor (typically letrozole) + CDK4/6 inhibitor (typically ribociclib, but could be palbociclib or abemaciclib)

• This is the "best shot" to control disease

Second-Line:

• Historically: Fulvestrant

• Emerging: Oral SERDs

EMBER-3 Study (Imlunestrant)

• Led to imlunestrant approval

• Also tested combination with abemaciclib

• Key Finding: Combination showed significant benefit regardless of ESR1 mutation status

• FDA Approval Puzzle: FDA only approved imlunestrant as single agent for ESR1-mutated disease, despite combination data

• Dr. Esteva awaits more information on why combination wasn't approved

SERENA-6 Study (Camizestrant): Preemptive Switching Strategy

Innovative Design:

• Thousands of patients screened using liquid biopsy for ESR1 mutation

• Once mutation detected, patients randomized to:

  • Continue current AI or tamoxifen, OR

  • Switch to camizestrant

Results:

• Significantly better results with preemptive switching

• Also showed benefit in PFS2 (progression-free survival after next line of therapy)

Clinical Implications:

• If approved, Dr. Esteva would implement serial ctDNA testing

• Would switch therapy based on molecular evidence before radiographic progression

• Controversy exists: Does early switching delay things or use up a line unnecessarily?

• Evidence suggests benefit persists through subsequent lines

ESR1 Mutation Testing Strategy

Current Practice:

• Next-generation sequencing on all newly diagnosed metastatic breast cancer patients

• Continue liquid biopsies after starting treatment

• If ESR1 mutation emerges: Consider elacestrant or camizestrant second-line

• If PI3K mutation found: Consider PI3K or AKT inhibitor like capivasertib

Future Considerations:

• If imlunestrant + CDK4/6 becomes frontline, treatment sequencing becomes more complex

• Third-line options becoming "blurred"

• Studies exploring SERDs + everolimus (evERA study)

ELEVATE Trial

• Umbrella trial testing elacestrant in multiple combinations:

  • Elacestrant + everolimus

  • Elacestrant + abemaciclib

  • Elacestrant + palbociclib

  • Elacestrant + capivasertib

• Results awaited with interest

Triple-Negative Metastatic Breast Cancer

Notable Absence

Victoria points out that the "What Will You Do in Clinic Monday?" session at San Antonio didn't discuss triple-negative disease at all due to time constraints, despite important developments.

Antibody Drug Conjugates: New First-Line Options

Sacituzumab Govitecan (Trodelvy)

Study Results:

• Compared to chemotherapy in first-line setting

• Showed significant improvement in both:

  • Progression-free survival

  • Overall survival

Clinical Status:

• NCCN guidelines: Preferred Category 1 (highest evidence level)

• Dr. Esteva's current first-line choice for triple-negative disease

Mechanism:

• Targets TROP2 protein

• Given on days 1 and 8 of 21-day cycle

Toxicity Profile:

• More myelosuppression (neutropenia)

• More GI side effects

• Can be complicated to administer due to bone marrow reserve issues

Datopotamab Deruxtecan (Dato-DXd)

Study Results:

• Also targets TROP2

• Showed improvement in progression-free survival

• Overall survival data not yet mature

Toxicity Profile:

• Different from sacituzumab

• Requires eye monitoring

• Mucositis concerns

• Generally considered better tolerated by some patients

Comparison: Both effective, targeting same protein (TROP2), but different toxicity profiles allow for personalized selection.

Integration with Immunotherapy

Current Standard (PD-L1 Positive):

• Nab-paclitaxel (Abraxane) + pembrolizumab

Emerging Approach:

• ASCENT-04 Trial: Sacituzumab + pembrolizumab

• Showed better results than standard chemotherapy

• Not yet FDA-approved but likely based on trial results

• Rationale: ADC chemotherapy payloads induce immunogenic cell death, potentially enhancing immunotherapy response

Treatment Selection by PD-L1 Status:

• PD-L1 Negative: TROP2-targeted ADC (sacituzumab or dato-DXd)

• PD-L1 Positive: Likely moving toward TROP2 ADC + immunotherapy combination

Expanding HER2-Targeted Therapy

HER2-Low and HER2-Ultralow:

• Trastuzumab deruxtecan (Enhertu) now works in patients previously classified as "HER2-negative"

• Includes patients with minimal HER2 staining (formerly called "zero")

• Paradigm shift: Expands treatable population from ~20% to potentially 60-70% of breast cancers

• Mechanism: Deruxtecan's bystander effect kills neighboring cells even with low target expression

Clinical Experience:

• Dr. Esteva treating patient with HER2-ultralow disease with good response

• Acknowledges subjectivity in pathology interpretation between "zero" and "ultralow"

PARADIGM Trial:

• Phase 2 trial at Yale

• Testing Enhertu in completely HER2-negative (zero) patients

• Results awaited

Future Directions

New Targets in Development:

• NECTIN4: Enfortumab vedotin (approved in bladder cancer) showing activity in triple-negative breast cancer

• LIV1: Another target under exploration

• Multiple posters at San Antonio exploring various targets

Androgen Receptor:

• Present in some triple-negative (and other) breast cancers

• Area of investigation but results "not spectacular"

• Studies from Memorial Sloan Kettering and Translational Breast Cancer Research Group showed relatively mild responses

• Question remains: Is androgen receptor a true driver or just present?

• Not as potent as estrogen receptor in driving disease

Artificial Intelligence and Technology

Dr. Esteva was particularly fascinated by AI developments at the symposium:

Foundational Models:

• Both academic laboratories and private companies developing AI assays

• Machine learning integrating pathologic and prognostic factors

• Potential to predict prognosis better than current tools like Oncotype

• Applications in pathology, radiology, and drug development

Clinical Implementation:

• AI will play major role in future of oncology

• Improving interpretation of complex data

• Enhancing precision medicine approaches

Key Themes and Takeaways

1. Personalization is Paramount

Despite impressive trial results, Dr. Esteva emphasizes:

• Not all patients should be treated the same

• Clinical trials enroll highly selected "cancer Olympians"

• Real-world patients have comorbidities requiring individualized approaches

• Oncology is both science and art

2. The Complexity of Randomized Trials

• Each trial answers one question but raises three more

• Secondary endpoints provide additional insights but not definitive answers

• Real-world evidence increasingly important to complement trial data

3. Quality of Life Considerations

• Treatment efficacy must be balanced with tolerability

• Patient-reported outcomes increasingly important in trial design

• Maintenance strategies can preserve quality of life while maintaining disease control

4. Molecular Profiling is Essential

• Next-generation sequencing for all newly diagnosed metastatic patients

• Serial liquid biopsies to detect emerging resistance mechanisms

• Actionable mutations guide treatment selection (ESR1, PIK3CA, etc.)

5. The ADC Revolution

• Antibody drug conjugates transforming treatment across all subtypes

• Multiple targets (HER2, TROP2) and payloads available

• Sequencing after ADC progression remains unclear

• More targets in development (NECTIN4, LIV1)

6. Combination Strategies

• Moving away from monotherapies

• Rational combinations based on biology (e.g., ADC + immunotherapy)

• Challenge: Managing overlapping toxicities

• Need for studies defining optimal sequences

7. Brain Metastasis Prevention

• Major advance with tukatinib in HER2+ disease

• Addresses significant patient fear

• Questions about screening strategies remain

• Transcript

  [03:13:00] Victoria: Welcome to the first episode of 2025! As we step into this new year, we're filled with hope and optimism – not just for fresh beginnings, but for the incredible advances in breast cancer treatment that continue to transform lives.

  This year promises to be groundbreaking in oncology, and what better way to kick off than by diving into the latest research from the San Antonio Breast Cancer Symposium. The progress we're seeing – from new antibody drug conjugates to oral SERDs, from improved brain metastasis prevention to personalized treatment approaches – reminds us that every new year brings us closer to better outcomes and longer, healthier lives for people living with metastatic breast cancer.

  So here's to 2025: a year of continued innovation, hope, and the promise that science keeps delivering. Let's make this year count.

  Dr. Francisco Esteva, I am so incredibly happy to see you [03:14:00] today and have a chance to speak with you about the San Antonio Breast Cancer Symposium. For full disclosure, Dr. Esteva and I met on the plane going home from San Antonio and we got to talking and we realized that we have a lot in common.

  And I invited, well, actually, you know how I am, I forced Doctor Esteva to come today and to talk with us about the San Antonio Breast Cancer Symposium, and especially about metastatic breast cancer findings from the San Antonio Breast Cancer Symposium. But first. First, I would love to ask you to introduce yourself and tell us about yourself.

  And there's one question I used to ask all the time. I kind of stopped doing it, but I will ask you anyway. Why did you decide to become a breast oncologist? [03:15:00]

  [03:15:00] Dr. Francisco Esteva: Yeah, thank you, Victoria. It was really nice meeting you on our way back from San Antonio. And we had a great conversation and it's really a pleasure to share this time with you.

  I'm a medical oncologist. And I became Interested in breast cancer when I was a fellow many years ago at Georgetown University with Dr. Mark Lipman and others at the helm. They had a very good breast cancer program. And I became really interested in understanding the molecular biology and the research about breast cancer and also the human aspects of it.

  It's a cancer that we can cure in many situations, and even if a patient develops metastatic disease, we can prolong life and provide a good quality of life.

  [03:15:45] Dr. Francisco Esteva: So at the time when I was a fellow, we were starting to test the new monoclonal antibodies like Trastuzumab. Herceptin became approved soon after I finished my fellowship and then I moved to MD [03:16:00] Anderson Cancer Center in Houston, where I spent the next 16 years and did a lot of research in metastatic disease and metastatic breast cancer.

  A lot of it in HER2+ disease, but also in predictive and prognostic biomarkers and many other therapies.

  [03:16:15] Dr. Francisco Esteva: That was was probably the most productive time of my life. Then 12 years ago, I moved to New York, to NYU, where I led the breast medical oncology program for about six years or so.

  And now I'm at Lenox Hill Hospital which is part of Northwell Health, also focusing on breast cancer, building the best program we can build with an effort to serve the community and also offer clinical trials.

  We have strong collaborations with researchers in the laboratory, but we are focusing on the patients and patients are at the center of all we do at Northwell. So thank you again.

  [03:16:53] Victoria: , That's wonderful. And you didn't tell us about something else. You have a YouTube channel. So tell [03:17:00] us a little bit about that.

  [03:17:01] Dr. Francisco Esteva: Yeah, about two years ago I started my own YouTube channel with the hopes to educate cancer patients. I see patients in clinic and it's very hard to sometimes remember all the things we talked about. There's a lot of information in the internet and YouTube and elsewhere.

  A lot of it for doctors, but I felt there was a gap in that patients need very detailed and simple information. So the goal of my channel is to synthesize and provide very complex information in simple terms so anyone can understand. And also it stays there so you can go back and rewatch it if you are interested in what stage you have or what kind of tumor you have.

  I'm trying to break it down and with, again, the hope to educate patients, but not so much the doctors. My audience is guided for patients. So your input would be very helpful in that sense.

  [03:17:54] Victoria: Well, let me tell you, I have checked it out and I really liked it. I consider myself [03:18:00] an expert, so I was watching it with prejudice. It's really good. I enjoyed it, and there was some stuff that I actually learned. I think this is a very, very useful, tool for us. And of course, here on the podcast, we do exactly the same. We try to disseminate information for our community.

  So we're symbiotic, aren't we? So this is a good way to start.

  Great.

  So let's begin. San Antonio was, interesting, wasn't it?

  I think the best way for us is to break it down by subtype,

  [03:18:37] Victoria: But before we start with that, just give me, , your. Overview of what you thought of the San Antonio Breast Cancer Symposium this year, and what studies did you think were important for us to talk about?

  [03:18:54] Dr. Francisco Esteva: The San Antonio Breast Cancer Symposium, to me is the premier, symposium in the world. I mean, [03:19:00] we see the latest advancements in breast cancer, both in patients with early stage and metastatic disease, and also how biomarkers should be used properly in all situations. And a big emphasis on translational research, which is the backbone where most, discoveries are made, translated into the clinic, and ultimately we move them into clinical trials.

  So I always learn a lot about the basic research, the new technologies, next generation sequencing. There was a lot of data actually this year about artificial intelligence that I found fascinating using foundational models as well as how to interpret pathology in a way that we couldn't do before.

  So that was very interesting to me from the basic research and technology aspects of it, because the machine learning is going to play a major role in the future. I believe in pathology, radiology, drug development, et cetera. And [03:20:00] then in terms of clinical trials, which is what we can bring to the clinic on Monday, as we say, there were a number of studies that I thought were impactful.

  One of them was the lidERA study using giredestrant in the adjuvant setting in early stage breast cancer. Oral SERDs are making an impact in metastatic disease but the early stage is where we make the biggest impact overall.

  [03:20:24] Dr. Francisco Esteva: We also saw studies in the metastatic setting, a lot of new treatments are being developed. Two of them are already approved, elacestrant and imlunestrant are approved and imlunestrant was approved in 2025, not long ago.

  And then, camizestrant was presented at ASCO this year with the SERENA-6 clinical trial.

  I think the HER2CLIMB-05 in HER2+ was important. DESTINY-BREAST09 was also an important trial that just . Around the time of the San Antonio Symposium [03:21:00] was approved by the FDA.

  And talk about that. In the triple negative area, we saw a study using sacituzumab, compared to chemotherapy.

  But at ASCO we also saw similar studies looking at integration of ADCs and immunotherapy in triple negative disease,

  [03:21:19] Dr. Francisco Esteva: Mostly with PD-L1 positive tumors. And then in the estrogen receptor positive, oral SERDs is probably the area of most advances.

  But if we can match the HER2 and ER positive tumors, then we are starting to see also how can we integrate new therapies in the HER2+/ER+ disease as well, like the PATINA study and so on. So, lots of things to discuss, but I would say these were my main take home messages.

  [03:21:49] Victoria: What about the poster sessions? Did you have a chance to see any poster sessions, anything that struck you there?

  [03:21:56] Dr. Francisco Esteva: Yeah. In the poster sessions there's so many, and you run very [03:22:00] quickly.

  [03:22:00] Victoria: Yeah.

  [03:22:01] Dr. Francisco Esteva: A lot of translational research, studies that I thought were fascinating. What caught my eye mostly were the ai, artificial intelligence programs that are being developed.

  Both academic laboratories and private companies are developing these assays based on foundational models where they can actually have the machines learn how to integrate all these pathologic factors and prognostic factors and be even better than Oncotype, for example, in predicting prognosis.

  That is what caught my eye mostly on the posters, but then many other Phase 1/Phase2 trials, trials that don't make it to the big oral sessions, that look promising as well when we look at specific combinations of tyrosine kinase inhibitors with HER2 standard therapy.

  There are lots of new developments coming up. So yeah, very interesting area.

  [03:22:54] Victoria: Yeah, I'm glad you mentioned that because I was just thinking about this, recently , people living [03:23:00] with HER2+ breast cancer, may very well have PIK3CA mutations mutations in the PI3K/ mTOR pathway.

  About 30%, I think, but none of HER2+ patients right now are eligible for any of the clinical trials or any therapies. So it's nice to see that actually this is being considered and in fact, for me personally, what was the most striking thing is that now the triple positive disease is its own subtype.

  So in the past, when I was diagnosed 12 years ago with metastatic disease, we were just dumped together with the HER2+/HR-, because it was considered that the driver for our cancer was HER2. So it didn't matter , what our estrogen status was.

  [03:23:48] Dr. Francisco Esteva: It's actually good to see that it's giving us more options .Just To mention the PI3 kinase, that's an area, i've spent a lot of time, personally. We published our first paper in Cancer [03:24:00] Cell maybe in 2004, more than 20 years ago

  showing that PTEN loss, for example, was associated with Herceptin resistance.

  [03:24:50] Dr. Francisco Esteva: PTEN is a tumor suppressor gene that normally helps regulate the PI3K/AKT/mTOR pathway. When PTEN is lost or mutated, this pathway becomes hyperactive, [03:25:00] which can drive cancer growth and resistance to HER2-targeted therapies. This is why combining HER2 inhibitors with PI3K pathway inhibitors makes biological sense.

  And then as part of our SPORE grant in that same area many years ago, I published a paper, combining Trastuzumab with everolimus trying to block the mTOR pathway. Published that in JCO in the Journal of Clinical Oncology many years ago.

  So that's an area that I've had personally a lot of interest in the PI3 kinase pathway through PI3 kinase mutations, PTEN loss, PI3 kinase hyperactivation in different ways. Now we have so many better treatments to block the PI3 kinase. Alpelicib, for example, perhaps a little bit,

  too much toxicity in terms of the glucose metabolism. But now we have capivasertib that blocks AKT, and we are seeing more and more of these therapies that are safer in that area.

  The PI3K/AKT/mTOR pathway is one of the most commonly dysregulated pathways in breast cancer. Capivasertib targets AKT, which [03:26:00] sits downstream of PI3K, potentially offering efficacy with a more favorable side effect profile than direct PI3K inhibitors like alpelisib, which causes significant hyperglycemia.

  But as you said in the HER2+ tumors is not, where they're actually studied the most is mostly in the ER+/HER1-.

  I've tried to use it in some patients with like you who had ER positive, HER two positive disease. And sometimes insurance companies don't approve it because it's not within the label. But I think it's an area we need to explore more.

  [03:26:32] Victoria: Absolutely. Especially it's clear that in the HER2 space, we have now competition between two first lines.

  Right. And we'll talk about this. But then what happens after a person progresses on, uh, antibody drug conjugate. It's not very clear , what the next lines are. The line three, four and further.

  [03:26:53] Dr. Francisco Esteva: Right, right.

  [03:26:54] Victoria: And there was a poster at San Antonio this year, that Sarah Tolaney and people at [03:27:00] Dana-Farber put together that shows that the subsequent treatments after the antibody drug conjugate are not all that effective.

  And I think there is a lot to discover here too. So let's just talk about these first lines in HER2 positive disease. So as you just said, trastuzumab deruxtecan, DESTINY-BREAST09, uh, was approved by the FDA. So is that our first line? Is that what you're gonna do in the clinic now?

  [03:27:37] Dr. Francisco Esteva: Yeah. Yeah. That's gonna be our first line just to summarize for the audience, the DESTINY-BREAST09 trial was a global randomized Phase 3 study, and they looked at Trastuzumab Deruxtecan or TDXd or Inhertu is the same name.

  Plus pertuzumab compared to the standard taxane, trastuzumab and pertuzumab, what we call [03:28:00] THP. And it was superior in terms of progression-free survival.

  [03:28:04] Dr. Francisco Esteva: A significant difference like 40 months compared to 27 months. PFS with a hazard ratio of 0.56.

  For context, a hazard ratio of 0.56 means there's a 44% reduction in the risk of disease progression or death. This is a substantial clinical benefit – the lower the hazard ratio, the better the treatment performs.

  So almost doubled, the probability of PFS, the overall survival still not mature, the CLEOPATRA regimen based on the CLEOPATRA study where we added Pertuzumab to Trastuzumab and taxane

  was a major breakthrough years ago. I remember when we published the first preclinical study, that showed Trastuzumab and Pertuzumab synergy. We published that in cancer research in 2004, something more than 20 years ago in the laboratory, that was in my lab at MD Anderson. [03:29:00] And then, that moved very quickly into the clinic.

  THP showed significant improvement in PFS compared to TH so adding pertuzumab, and now we have another major leap in terms of improvement of PFS because a PFS of 40 months on first line therapy, it's a lot, it's

  [03:29:20] Victoria: unbelievable. When I

  [03:29:21] Dr. Francisco Esteva: was a fellow, the median survival for patients was two years overall.

  This is first line, HER2+, the most aggressive tumor- 40 months, three and a half years, just on the first line. So that's a significant improvement. Now it comes with toxicity and so on, but we have to focus on the efficacy right now. So I think it will become

  my next first line treatment. We are just doing a study which will be closing soon. We were testing, uh, at Lenox Hill and other places in the US and also in Europe, a study called DEMETHER. Oh yeah. So we are the only site in New York [03:30:00] at the moment where we are giving TDXD or Inhertu for a number of cycles in the first line setting of metastatic HER2 positive disease.

  And then we would continue with Phesgo, which is Trastuzumab and Pertuzumab together as maintenance. And now with this new approval, we'll have to move to Inhertu plus pertuzumab, whether HER2 alone followed by trastuzumab, Pertuzumab would be better, the same -we don't know.

  That's the problem with this type of randomized trials, that they answer one question but you have three other questions and we are left with that study. So to answer concretely, I think yes, this will become the standard

  [03:30:39] Victoria: irrespective of the tumor burden,

  other things, I mean, look, the quality of life and I have talked to so many people on Inhertu , now that Inhertu is basically given to everyone at some point, right?

  Right, right.

  ER positive. HER2 negative, HER2 positive. Triple negative. Everybody [03:31:00] gets it. And the quality of life is not good.

  The side effects are tough, tough, tough.

  [03:31:07] Dr. Francisco Esteva: I know and that was also my impression. But then in San Antonio, they presented a study looking at patient reported outcomes on the DESTINY-BREAST09 trial. And the quality of life was similar for both Inhertu and THP, which I thought like you, that with Inhertu you would , you know, see more gastro intestinal side effects like nausea, vomiting, things we can manage with medication.

  But you see more of that. With TDXD, they saw less skin changes, mucosal changes, but in terms of fatigue, pain control and maintenance of general function was very similar. Which was a little bit surprising because THP, the problems it causes also neuropathy with the weekly Taxol/Taxotere.

  Inhertu can do that also after some time. [03:32:00] If you give it until progression is a lot, you know, that's why the other approach we were doing with the DEMETHER study, it's a small study . We were just giving a small number of cycles, let's say six cycles,

  Which Are manageable. If patients have a great response, then we would keep them on HP -Trastuzumab- Pertuzumab. I think that's still a valid approach,

  [03:32:20] Victoria: absolutely.

  [03:32:21] Dr. Francisco Esteva: Patients because of their quality of life. But, it's hard to ignore when you get a trial like that and then the FDA approval, but personally,

  I would feel comfortable if someone doesn't have a big load of disease to treat with Inhertu alone, get good response, then maintenance. I think that's still a valid approach with hormone therapy if needed with CDK4/6 inhibitor with tukatinib we'll talk about all of these things.

  [03:32:45] Victoria: Yeah. So

  [03:32:45] Dr. Francisco Esteva: I just don't think should be the standard, meaning everyone should be treated the same.

  [03:32:50] Victoria: Right. Right. we were just talking about the CLEOPATRA protocol I guess this is the only first line treatment in the whole breast cancer [03:33:00] regimen where the maintenance is considered, I mean, most other treatments that I know of you take it until the progression. Yeah. CLEOPATRA is different right? There,

  for whatever reason, it was decided on six to eight first induction taxane treatments I guess six months. And my understanding is that the reason that six months was chosen was because of the neuropathy by that time, and that's when it was dropped. My example, I don't really talk very much about it these days, and I told you on the plane, I was treated differently than most people.

  I was on the CLEOPATRA induction for five years. And, and that's a lot too much

  [03:33:43] Dr. Francisco Esteva: for most people. Yeah, that's

  [03:33:44] Victoria: a lot. , That's too much for

  [03:33:45] Dr. Francisco Esteva: most people. You were able to tolerate it, which is great. Yeah. For someone who can tolerate, I don't mind. But we need to personalize treatment.

  [03:33:53] Victoria: Yeah.

  [03:33:53] Dr. Francisco Esteva: If you can tolerate it, great, but most people can't.

  [03:33:56] Victoria: So this is something I wanted to ask you and I haven't [03:34:00] seen it anywhere and there was no comparison. So when they did this trial where they compared the two first line treatments, the CLEOPATRA protocol and the TDXD, obviously, when the two curves broke after six months, you could see CLEOPATRA went down while, TDXD continued to do better. So my question is, what would've happened had they run a different trial for CLEOPATRA, not six months, but say a year.

  [03:34:29] Dr. Francisco Esteva: It's very high, again, when we do randomized trials, we answer one question, right? And then we have a bunch of secondary endpoints, but the primary endpoint is the key you're trying to answer. And then these other things we don't really know. So that's the science part.

  But then, oncology is

  also on art. We need to adjust it to each patient. I don't think many people could tolerate THP because when we used Taxol again, I was involved in the first study many years ago, combining weekly axel with [03:35:00] trastuzumab.

  Mm-hmm. And then weekly Taxotere with Trastuzumab. And it's very hard to give it in terms, oh, Taxotere is horrible. Taxotere is very hard. Even with Taxol, you get to the point that neuropathy maybe limiting,

  But that's a major limitation. With Inhertu, you can also have

  [03:35:16] Victoria: Right.

  [03:35:16] Dr. Francisco Esteva: Neuropathy And somehow also we have to remember, patients who are eligible for these trials are really a highly selected population.

  [03:35:27] Victoria: That's right.

  [03:35:28] Dr. Francisco Esteva: They're

  [03:35:28] Victoria: Olympians. Right.

  [03:35:29] Dr. Francisco Esteva: Cancer

  [03:35:30] Victoria: Olympians,

  [03:35:31] Dr. Francisco Esteva: , So then when we get to the community and I see patients who may be elderly or maybe have heart problems, kidney problems, liver problems , still we need to treat them. That's where there was also some interest in San Antonio talking about real world evidence as opposed to

  randomized

  trials, which I think is important , and so we need to take all these things into consideration when we see patients with metastatic disease.

  [03:35:54] Victoria: No, you're right. But there was a little, change though for [03:36:00] CLEOPATRA as well. And I'm talking about the HER2CLIMB-05 was it that was presented as the first line maintenance

  addition of Tukatinib

  [03:36:11] Dr. Francisco Esteva: Tukatinib. Yes.

  [03:36:13] Victoria: And then of course, we talked about this earlier, the PATINA trial, adding palbociclib to CLEOPATRA maintenance regimen. So that makes a big difference. It looks like, pure CLEOPATRA is gone. That's it. There won't be any more THPs.

  Right,

  [03:36:32] Dr. Francisco Esteva: right, CLEOPATRA was interesting in other ways. For example, patients with ER-positive breast cancer did not receive hormone therapy, which is very strange . Even then there was a benefit. So, nowadays we give tamoxifen or an AI to patients with ER-positive disease.

  But in the CLEOPATRA study, that was not mandatory.

  That was up to the physicians, which again, I find a little bit strange to say the least. So now with the PATINA study where we added the CDK4/6 [03:37:00] inhibitor to hormone therapy, we are adding two things to the CLEOPATRA, the hormone therapy plus the CDK4/6.

  So it's, significant improvement by adding palbociclib .

  Now , the Tukatinib study is also interesting. Tukatinib is a very interesting molecule that is a tyrosine kinase inhibitor.

  We used to have lapatinib that blocked the HER2 tyrosine kinase and EGFR. It kind of fell off the radar, because, TDM1 became more effective than capecitabine and Lapatinib.

  Tukatinib Is different. It's a pure, more selective, HEr2 tyrosine kinase inhibitor.

  So HER2 is a receptor on the cell surface that inside activates this tyrosine kinase that then activates the PI3 kinase, AKT/mTOR, et cetera.

  To clarify the mechanism: Tukatinib is a highly selective HER2 tyrosine kinase inhibitor that crosses the blood-brain barrier effectively. Unlike earlier TKIs like lapatinib, which also inhibits EGFR and causes more GI toxicity, [03:38:00] Tukatinib's selectivity for HER2 provides better CNS penetration with fewer off-target effects. This makes it particularly valuable for preventing and treating brain metastases.

  So it's a very specific blocker of the HER2, much more specific than let's say, neratinib or Lapatinib that blocks EGFR, neratinib- a little bit of EGFR and also HER4.

  And the fact that they are now showing this significant improvement, it's something to keep in mind. There was benefit both in the ER positive and the ER negative patients, more in the hormone receptor negative patients.

  So basically patients have received the THP regimen and then added Tukatinib to the HP or not in HER2CLIMB-05. And, you know ,there was a significant improvement in PFS. So in the ER negative was 44%.

  [03:38:49] Victoria: Yeah.

  [03:38:50] Dr. Francisco Esteva: Reduction in the risk of progression or death. And with a 12 month improvement in PFS and the ER positive was 27, percent relative risk [03:39:00] reduction in PFS with a seven month improvement, which is also significant.

  So that is clearly an option. Actually, Tukatinib was also shown to be effective in the prevention of brain metastasis.

  [03:39:12] Victoria: Exactly.

  That's what I was gonna ask.

  [03:39:14] Dr. Francisco Esteva: Helped in both in patients with and without brain metastasis, but something oncologists have in the back of our minds if there is a question about that, and which patients should we screen with MRIs or not?

  That's another area. Well, well,

  [03:39:26] Victoria: Let's talk about that for a second we can talk about this later at some point in more detail, but do you screen?

  [03:39:34] Dr. Francisco Esteva: I don't screen right now. I might begin screening a little bit more, but right now, I don't screen with MRI of the brain. The standard guideline is to only do an MRI of the brain if the patient has neurological symptoms.

  But you can argue a patient with high risk features, for example, someone with extensive visceral disease, aggressive tempo that is [03:40:00] progressing very quickly. And of course if they have any neurological symptoms, we have to do that, but without any symptoms there is some experts that are proposing we should screen more patients with brain mRI.

  [03:40:13] Victoria: What would be the reason not to do it?

  [03:40:17] Dr. Francisco Esteva: Well, it's just another test . i understand why there may be some hesitance, but it wouldn't hurt, I don't think, but it's a lot of testing we do already .

  [03:40:26] Victoria: Yeah. And yeah. So what would be the cadence? How often would you have to run this test? Every six months?

  [03:40:32] Dr. Francisco Esteva: I mean personally, if we were to screen patients who develop metastatic HER2 positive disease, for example, and they have no evidence of disease, then I would not repeat it.

  I would just

  [03:40:43] Victoria: just do it once and

  [03:40:45] Dr. Francisco Esteva: that symptoms, yeah, if they have symptoms, you do it. You may choose to use Tukatinib anyway.

  [03:40:51] Victoria: Yeah. I have to tell you that for people living with, uh. HER2 disease, that's the biggest fear. It's always [03:41:00] been the biggest fear, and I guess the triple negative is very similar to that.

  But in our space, in HER2 space, just the fear of developing brain mets is so huge that having Tukatinib is a tremendous improvement in the quality of life for people who are so worried about the future.

  [03:41:20] Dr. Francisco Esteva: Right. , So in that case, why do you need to screen if you're gonna treat the patient anyway?

  [03:41:24] Victoria: Yeah, no, it's true,

  [03:41:26] Dr. Francisco Esteva: The study was with THP plus Tukatinib, now we're gonna do Inhertu pertuzumab, now we're starting mixing things. It's gonna be interesting how we apply this.

  [03:41:33] Victoria: Now we also have PATINA plus tukatinib plus, uh, Endocrean treatment plus

  yeah.

  Whatever it's gonna be what, not triplets, but five drugs and lots of options and the side effects will multiply. But you're right ,it looks like there won't be any more monotherapies, would you still consider giving a... and now let's go [03:42:00] back to ER-positive disease.

  Would you consider giving a monotherapy to your patient at some point in the beginning or as a second line? Just an oral SERD? I mean, that's what was approved there, right? imlunestrant and elacestrant at this point have been approved for ESR1 mutated cancers as monotherapies. Right now you have to, but is that something you would consider doing anyway?

  [03:42:27] Dr. Francisco Esteva: Yeah because we are talking about second line therapy in the palliative setting, if you will, we have to be careful. I'm a little bit more inclined to use combination and more, , I don't like the word, but more aggressive therapy in the first line.

  That's your best chance, your best shot.

  We're talking about a lot of combinations, but again, that's your best chance to control the disease, I think . So my go-to in patients with metastatic ER-positive, HER2 negative disease has been an AI plus a CDK4/6 inhibitor.

  [03:42:59] Dr. Francisco Esteva: I [03:43:00] generally use letrozole and Ribociclib, but

  could be palbociclib or abemaciclib. And then fulvestrant has been the second line, ESR1 mutation. As you know, based on the, EMBER-3 study, the one that led to the imlunestrant approval. In that study, they also combined it with Abemaciclib and there was a significant benefit for the combination, regardless of the ESR1 mutation.

  So that could become the second line, but it's not FDA approved yet.

  [03:43:32] Victoria: So I have to ask you related to that, So, SERENA-6 trial had a switch option, right? , They tested. Was that camizestrant? There are so many of them. I get confused. So they tested camizestrant Yes.

  With ongoing liquid biopsies and were looking for a developing ESR1 mutation.

  [03:43:55] Victoria: And once noticed molecularly, not on the scans they would [03:44:00] switch a patient to the next line. Yes. Which is camizestrant. Yes. So my question now related to what we were talking about a second ago.

  If the EMBER trial showed that the combination did well, which one Was that? imlunestrant. imlunestrant, yes. I and

  [03:44:19] Dr. Francisco Esteva: Abemaciclib. Yes.

  [03:44:20] Victoria: Did. Pretty well irrespective of the ESR1 status, is it really worth testing people for ESR1 anymore?

  [03:44:32] Dr. Francisco Esteva: Well, i'm a little bit surprised that the FDA only approved imlunestrant as a single agent based on that trial. And I don't know why.

  [03:44:41] Victoria: Yeah, they have

  [03:44:41] Dr. Francisco Esteva: data. We don't have all the data and, so we need to wait and see why that's the case and why was not approved with Abemaciclib, regardless of ESR1 mutation.

  So probably if it does, and then it's gonna be an issue. Now the camizestrant study is a little bit different in that you are trying to [03:45:00] intervene earlier,

  [03:45:01] Victoria: right?

  [03:45:01] Dr. Francisco Esteva: , So with the imlunestrant and abemaciclib, we'll see how it's approved, if it's frontline second line, but generally we've used these SERDS in the second line setting because we use the CDK4/6 with an AI in the frontline setting.

  Now, if this becomes the frontline

  [03:45:16] Victoria: mm-hmm.

  [03:45:18] Dr. Francisco Esteva: Then yeah, we'll have to discuss and see what we do next.

  We always do next generation sequencing on all patients who are newly diagnosed with metastatic breast cancer. That makes sense . If we're gonna use a CDK4/6 plus a SERD, like imlunestrant, for example, then

  I would still do liquid biopsies afterwards. You would to see what mutations come up. If there is an ESR1 mutation that perhaps was not there before then I would still consider elacestrant or camizestrant as an option second line. And then, if you find a PI3 kinase mutation, you can consider a PI3 kinase or an AKT inhibitor, like a capivasertib and, and so on.[03:46:00]

  Third line just becomes a little bit more blurred as to what to do. We are seeing these studies with SERDS plus Everalimus, like the evERA study and things like that.

  [03:46:09] Victoria: What was your take, in general, if this were approved, would you consider switching your patient just based on the liquid biopsy showing that there is ESR1 mutation before it shows up on the scans?

  [03:46:26] Dr. Francisco Esteva: I think so. So that's the SERENA-6 study that, thousands of patients were screened using liquid biopsy for ESR1 mutation.

  Once they found the mutation, patients were randomized to camran or continuation of an AI or Tamoxifen that they were on under camizesatrant.

  The SERENA-6 design is particularly innovative because it uses ctDNA monitoring to detect ESR1 mutations before radiographic progression. This preemptive switching strategy aims to overcome endocrine resistance earlier, potentially improving outcomes compared to waiting for clinical or radiographic progression. [03:47:00] The PFS2 endpoint – progression-free survival after the next line of therapy – helps assess whether early switching truly benefits patients long-term.

  So much better results. If that's approved, I would, I would You would

  [03:47:12] Victoria: do it?

  [03:47:13] Dr. Francisco Esteva: Yeah. It would lead to more testing, but, , I would do that. The only confounding there is that again, if imlunestrant is approved with the CDK4/6 frontline,

  But if , the camizestrant is approved based on the SERENA-6, which is likely to be approved since that was an FDA registration trial,

  I would, be compelled to do serial, ctdna testing. I know there's some controversy as to, is that delaying things or Right. And,

  [03:47:40] Victoria: and sense using up a line.

  [03:47:43] Dr. Francisco Esteva: Right. So, so if you were to do it in sequence or a little bit later, would that impact the overall survival? We don't know.

  The best evidence they have is called the PFS two. The progression-free survival two After the first progression. And that also showed benefit for patients on [03:48:00] camizestrant. So I think, it is good to have options.

  [03:48:03] Victoria: Well, and there was a phase two trial reported out, the ELEVATE trial, which is interesting.

  It was an umbrella trial of elacestrant with many different combinations.

  [03:48:15] Dr. Francisco Esteva: Yes. So

  [03:48:15] Victoria: that would be very interesting to see what the results of that would be.

  [03:48:19] Dr. Francisco Esteva: Yeah, the ELEVATE study, , combined elacestrant with everolimus, elacestrant with abemaciclib

  [03:48:26] Victoria: The picture looks bright. Yeah.

  So let's talk about the subtype that's not as bright as the other two, the triple negative.

  And in fact, the session at the very end of the San Antonio conference, what will you do in the clinic on Monday? They didn't even talk about triple negative at all. They didn't have time to talk about it, and they didn't talk about it at all. But there is something new. Now we have a definitive new first line antibody drug conjugates for triple negative,

  [03:48:59] Dr. Francisco Esteva: [03:49:00] yeah. The sacituzumab govitekan study that compared Trodelvy, basically Sacituzumab govitekan is the long name, to chemotherapy in the frontline setting showed a significant improvement in progression-free survival as well as overall survival.

  A similar compound called datoptomab the dato-DXd which is targeting the same protein called TROP2.

  Both sacituzumab govitecan and datopotamab deruxtecan are TROP2-directed ADCs, but they differ in their payloads and dosing schedules. Sacituzumab uses SN-38, the active metabolite of irinotecan, while dato-DXd uses the same deruxtecan payload as Enhertu. The different toxicity profiles – more myelosuppression and diarrhea with sacituzumab versus more nausea and ILD risk with dato-DXd – may influence treatment selection based on patient comorbidities.

  That one showed also improvement in progression-free survival, but not yet overall survival. So based on that, the NCCN guidelines, for example, put the, [03:50:00] sacituzumab as the preferred category one based on evidence as the first treatment to go.

  I just saw a patient yesterday in that same situation. Yeah, we decided to start on Sacituzumab.

  [03:50:11] Victoria: It has a better profile, doesn't it? It has a better side effect profile, at least based on my friends' experiences, it seems that that one is, better tolerated.

  [03:50:21] Dr. Francisco Esteva: It's different. So sacituzumab causes more myelosuppression, more neutropenia and so on.

  It's given on day one and day eight out of 21 days.

  And also hard to give sometimes 'cause a patient may have bone marrow reserve is not as good I find a little bit complicated and also it may cause more GI side effects. The other one, the datopotomab has other issues.

  Like we have to check the eyes and things like that and mucocitis , but at the end of the day we can manage the toxicities and we have to pick one right now. I think they're both effective targeting TROP2, but that's where we are. So we have that frontline [03:51:00] mostly for the triple negative breast cancer, in my opinion, with a PDL1 negative. Tumors . And then if they have PDL1 positive, it's probably going to be the same thing. TROP2 with immunotherapy, right now we are using Abraxane or Nab-Paclitaxel with pembrolizumab, but there is another study showing that if you combine Sacituzumab with pembrolizumab,

  The rationale for combining ADCs with immunotherapy is compelling: chemotherapy payloads from ADCs can induce immunogenic cell death, releasing tumor antigens and creating an inflamed tumor microenvironment that may be more responsive to checkpoint inhibition. The ASCENT-04 data suggests this synergy is real, though we need to carefully monitor for overlapping toxicities, particularly pneumonitis from both the ADC and the PD-1 inhibitor.

  The Ascent O four trial showed also better results than, standard chemotherapy. I don't believe that's been FDA approved right now, but [03:52:00] it's likely to be based on the ASCENT-04 trial. The ASCENT-03 is the one that put, sacituzumab on the map.

  We also have in what we used to call triple negative, we can use Inhertu in patients with HER2 low or ultralow or zero plus,

  as it's called where there used to be HER2-negative ER/PR-negative, but now if they're HER2-negative but enough to have some HER2 staining in the immunohistochemistry, which used to be called zero, Inhertu also works

  The HER2-low and HER2-ultralow classifications represent a paradigm shift. We now know that even minimal HER2 expression – IHC 1+ or IHC 2+ with negative ISH, and even some IHC 0 cases with any membrane staining – can respond to T-DXd. This is because deruxtecan's bystander effect allows the payload to kill neighboring cells even with low target expression. It essentially expands the treatable population from 20% to potentially 60-70% of breast cancers.

  In those [03:53:00] patients. And I have a patient like that I'm treating now that she had a good response. I was a little bit skeptical. Again, as we said before, the patients on the trials are highly selected. This patient is responding and I chose that.

  But I mean between that and the zero plus is very subjective how the pathology cause, so there

  [03:53:17] Victoria: is a trial going on right now, out of Yale. It's called PARADIGM, it's phase two trial where they're actually testing people who are HER2-negative, completely zero, with Inhertu.

  [03:53:33] Dr. Francisco Esteva: We are making progress.

  [03:53:34] Victoria: So when is it gonna change? So right now we have a few antibody drug conjugates, but they all have either the same target.

  There're basically , two targets now, right? TROP2 or HER2, or they have very similar payload. When are they gonna add more, targets and newer chemos?

  Have you heard of anything else?

  [03:53:55] Dr. Francisco Esteva: Yeah. There, are many targets, saw a poster, [03:54:00] for example, targeting NECTIN4. There is another one, LIV1.

  So there are other targets that they're exploring in triple negative disease. The NECTIN4- it's called Enfortumab vedotin that's been approved in bladder cancer seems to have activity in triple negative disease as well. So that's something I'm looking forward to see more studies.

  [03:54:21] Victoria: Before we go, I wanted to ask you one more thing, and I don't know if there was anything in San Antonio about it, but some people with triple negative breast cancer have androgen receptor. It's not only triple negative, I guess ER-positive and HEr2-positive can have androgen receptor.

  But is there anything actionable for people who are androgen positive?

  [03:54:46] Dr. Francisco Esteva: It's an area of investigation. There's been a lot of interest in targeting the androgen receptor. But the results have not been spectacular, I don't think, because , for example, Sloan Kettering did a study.

  response was relatively mild. , [03:55:00] The Translational Breast Cancer Research Group also did a study. So I'm not that impressed, meaning the androgen receptor may be there, but is it a driver? Is it driving the disease? ? Not clear to me. It's almost like the ER, but it's not as potent or strong as the estrogen receptor.

  [03:55:17] Victoria: Thank you. We've covered everything very nicely, don't you think?

  [03:55:21] Dr. Francisco Esteva: I think so. Yeah. You're an expert.

  [03:55:24] Victoria: We did a great job. I loved it. So what are we gonna talk next time about then? We've covered everything.

  [03:55:32] Dr. Francisco Esteva: We'll find something,

  [03:55:33] Victoria: we'll find something to talk about. So thank you so much for being here and I expect you to come again and this is going to be our first episode of the New Year.

  What an incredible conversation! Today, Dr. Francisco Esteva walked us through the most significant findings from the San Antonio Breast Cancer Symposium, and the progress is truly remarkable.

  We covered groundbreaking developments across all breast cancer [03:56:00] subtypes: In HER2-positive disease, we discussed the DESTINY-BREAST09 approval of trastuzumab deruxtecan plus pertuzumab as a new first-line standard, the HER2CLIMB-05 study showing Tukatinib's promise for brain metastasis prevention, and the PATINA trial adding CDK4/6 inhibitors to the mix.

  For hormone receptor-positive disease, we explored the exciting world of oral SERDs – imlunestrant, elacestrant, and camizestrant – and how liquid biopsies are helping us personalize treatment by detecting ESR1 mutations early.

  And in triple-negative breast cancer, we discussed how antibody drug conjugates like sacituzumab govitecan are finally giving us better first-line options, along with the integration of immunotherapy.

  The future of metastatic breast cancer treatment is about personalization, combination therapies, and catching resistance before it shows up on scans. It's about giving people more time with better quality of life.

  If you found this episode valuable, please subscribe to our podcast, share it with others in the breast cancer community, and check [03:57:00] out Dr. Esteva's YouTube channel where he breaks down complex cancer information for patients.

  Before we go, an important disclaimer: This podcast is for educational and informational purposes only. The discussion you heard today represents general information about breast cancer research and treatment options. It is not medical advice and should not replace consultation with your own healthcare team. Every patient's situation is unique, and treatment decisions should always be made in partnership with your oncologist who knows your specific medical history, tumor characteristics, and individual circumstances. If you have questions about any of the treatments discussed today, please speak with your doctor.

  This podcast is produced and hosted by me, Victoria Goldberg. I want to extend my heartfelt thanks to Dr. Francisco Esteva for graciously accepting my invitation and taking the time to answer my questions with such depth and clarity. Your expertise and dedication to educating patients is [03:58:00] truly invaluable.

  Thank you to our amazing podcast team who works behind the scenes to bring you these conversations. And most importantly, thank you to you, our listeners, for being part of this community. Your engagement, your questions, and your commitment to staying informed inspire us to keep creating content that matters.

  Thank you for joining us for this first episode of 2025. Here's to a year of hope, progress, and continued breakthroughs. Until next time, stay informed and stay strong.

.

Trials Mentioned

• evERA (NCT05306340)

  This Phase III, randomized, open-label, multicenter study evaluates the efficacy and safety of giredestrant plus everolimus compared with the physician's choice of endocrine therapy plus everolimus in participants with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who have had previous treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) and endocrine therapy, either in the locally advanced/metastatic or the adjuvant setting.

• lidERA (NCT04961996)

  Phase III, randomized, open-label trial evaluating the efficacy and safety of giredestrant, an investigational oral selective estrogen receptor degrader (SERD), compared to standard-of-care endocrine therapy. 

  Presented at the 2025 San Antonio Breast Cancer Symposium (SABCS), the trial results demonstrated that giredestrant significantly improved outcomes for patients with early-stage breast cancer. 

  Key Trial Details (2025–2026 Update)

  • Patient Population: The study enrolled over 4,100 participants with medium- or high-risk Stage I–III estrogen receptor-positive (ER+), HER2-negative early breast cancer.

  • Primary Findings: At the interim analysis, giredestrant reduced the risk of invasive disease recurrence or death by 30% compared to standard endocrine therapy (Hazard Ratio [HR]: 0.70).

  • Survival Data: The 3-year invasive disease-free survival (iDFS) rate was 92.4% for the giredestrant group versus 89.6% for the standard-of-care group.

  • Safety & Tolerability: Giredestrant was well-tolerated with a safety profile similar to existing therapies. Common side effects included joint aches (arthralgia), hot flashes, and headaches. Notably, fewer patients discontinued giredestrant due to side effects compared to standard therapy (5.3% vs. 8.2%).

  • Significance: lidERA is the first Phase III trial of an oral SERD to show a statistically significant benefit in the adjuvant (post-surgery) setting for early breast cancer. 

  Comparisons in Results

  According to data presented by lead investigator Dr. Aditya Bardia, giredestrant showed superiority over both major types of standard endocrine therapy: 

  • vs. Aromatase Inhibitors: 27% reduction in risk (HR: 0.73).

  • vs. Tamoxifen: 47% reduction in risk (HR: 0.53). 

  The results support giredestrant's potential as a new standard-of-care option for this patient population. Findings are currently being shared with global health authorities for potential regulatory approval in 2026. 

• SERENA-6 (NCT04964934)

  The Landmark Phase III, randomized, double-blind study evaluating a proactive treatment strategy for HR-positive, HER2-negative advanced breast cancer. It is the first global registrational trial to use circulating tumor DNA (ctDNA) monitoring to guide a treatment switch before clinical or radiological disease progression. 

  Trial Strategy & Design

  • The Problem: Most patients on first-line therapy (aromatase inhibitors + CDK4/6 inhibitors) eventually develop resistance, often driven by ESR1 mutations.

  • The Approach: Patients were monitored via liquid biopsies every 2–3 months. If an ESR1 mutation was detected in their blood—even if their scans appeared stable—they were randomized to either:

    1. Switch to the investigational oral SERD camizestrant while continuing their current CDK4/6 inhibitor.

    2. Continue their original aromatase inhibitor (AI) plus the same CDK4/6 inhibitor. 

  Key Findings (Interim Analysis 2025)

  Results presented at the 2025 ASCO Annual Meeting showed significant clinical benefit for the early-switch group: 

  • Improved Progression-Free Survival (PFS): Switching to camizestrant reduced the risk of disease progression or death by 56% (HR 0.44).

  • Median PFS: 16.0 months for the camizestrant switch vs. 9.2 months for those who continued AI therapy.

  • Quality of Life: The switch significantly delayed the time to deterioration of global health status and quality of life (23.0 months vs. 6.4 months).

  • ESR1 Clearance: 100% of patients in the camizestrant arm saw a reduction in ESR1 mutation allele frequency after 8 weeks. 

  Safety and Status

  • Side Effects: Camizestrant was well-tolerated. The most notable side effect was photopsia (brief flashes of light), which was mild (Grade 1), reversible, and did not impact visual acuity or daily activities.

  • Regulatory Status: Based on these results, the FDA granted camizestrant Breakthrough Therapy Designation in 2025 for this specific setting.

  • Ongoing Monitoring: Data for overall survival (OS) and second progression-free survival (PFS2) remained immature at the time of the 2025 reports and will require further follow-up. 

• EMBER-3 trial (NCT04975308)

  A global, randomized, Phase 3 clinical trial evaluating the oral selective estrogen receptor degrader (SERD) imlunestrant(marketed as Inluriyo) for the treatment of ER+/HER2- advanced or metastatic breast cancer. 

  Key Trial Results (as of January 2026)

  The trial recently reported updated results at major 2025 oncology congresses (ASCO and SABCS), reinforcing the efficacy of imlunestrant-based regimens: 

  • Primary Findings:

    • Imlunestrant Monotherapy: Significantly improved progression-free survival (PFS) compared to standard-of-care (SOC) endocrine therapy (fulvestrant or exemestane) in patients with ESR1 mutations. Median PFS was 5.5 months for imlunestrant vs. 3.8 months for SOC.

    • Imlunestrant + Abemaciclib: This combination significantly improved PFS regardless of ESR1 mutation status compared to imlunestrant monotherapy. The median PFS for the combination reached 10.9 months.

  • Overall Survival (OS): An interim analysis showed a numerical but not yet statistically significant improvement in OS for patients with ESR1 mutations, with a median OS of 34.5 months for imlunestrant vs. 23.1 months for SOC.

  • Regulatory Status: Based on these data, the FDA approved imlunestrant (Inluriyo)for patients with ESR1-mutated advanced breast cancer. 

  Study Design & Population

  • Participants: 874 patients with ER+/HER2- advanced breast cancer who progressed on prior endocrine therapy (e.g., aromatase inhibitors).

  • Arms: Patients were randomized (1:1:1) into three treatment groups:

    1. Imlunestrant monotherapy (400 mg daily).

    2. Standard endocrine therapy (Investigator's choice of fulvestrant or exemestane).

    3. Imlunestrant + Abemaciclib (150 mg twice daily).

  • Endpoints: Primary endpoints included investigator-assessed PFS in ESR1-mutated and all-patient populations. 

  Safety and Quality of Life

  • Safety Profile: Imlunestrant demonstrated a favorable safety profile compared to other oral SERDs, with low rates of bradycardia and vision changes (photopsia). Common side effects included fatigue, nausea, and diarrhea.

  • Clinical Value: The all-oral regimen delayed the need for chemotherapy by approximately 5.5 months (monotherapy in ESR1m) to 12.2 months (combination in all patients). 

• HER2CLIMB-05(NCT05132582)

  This study is being done to see if tucatinib works better than placebo when given with other drugs to treat participants with HER2-positive breast cancer. A placebo is a pill that looks the same as tucatinib but has no medicine in it. This study will also test what side effects happen when participants take this combination of drugs. A side effect is anything a drug does to the body besides treating your disease.

  Participants will have cancer that has spread in the body near where it started (locally advanced) and cannot be removed (unresectable) or has spread through the body (metastatic).

  In this study, all participants will get either tucatinib or placebo. Participants will be assigned randomly to a group. This is a blinded study, so patients and their doctors will not know which group a participant is in.

  All participants will also get trastuzumab and pertuzumab. These are 2 drugs used to treat this type of cancer.

• CLEOPATRA(NCT00567190)

  a landmark Phase III clinical study that established the standard of care for first-line treatment of HER2-positive metastatic breast cancer. 

  Trial Overview

  • Purpose: To evaluate the efficacy and safety of adding pertuzumab (Perjeta) to a regimen of trastuzumab (Herceptin) and docetaxel (chemotherapy).

  • Participants: 808 patients with previously untreated HER2-positive metastatic breast cancer.

  • Design: A randomized, double-blind, placebo-controlled study. 

  Key Findings & Results

  The trial demonstrated unprecedented survival benefits for patients receiving the triple-drug combination: 

  • Overall Survival (OS): The addition of pertuzumab increased median overall survival by 15.7 months.

    • Pertuzumab Group: 56.5–57.1 months.

    • Placebo Group: 40.8 months.

  • Progression-Free Survival (PFS): Median PFS was significantly longer in the pertuzumab group (18.5–18.7 months) compared to the placebo group (12.4 months).

  • Long-term Survival: End-of-study analyses showed that 37% of patients in the pertuzumab arm were still alive at the 8-year mark, compared to 23% in the control arm.

  • Safety: The triplet regimen was generally well-tolerated, with no significant increase in cardiac toxicities (heart issues) compared to the standard dual therapy. 

  Clinical Impact

  • Standard of Care: The trial's success led to the FDA approval of pertuzumab for metastatic HER2-positive breast cancer.

  • Outcome Improvement: It transformed the prognosis of HER2-positive disease from an aggressive, poor-outcome subtype to one with manageable long-term survival

• DESTINY-Breast09

  A landmark phase 3 clinical trial evaluating Enhertu(trastuzumab deruxtecan; T-DXd) as a first-line treatment for patients with HER2-positive metastatic breast cancer. 

  Key findings presented in 2025 demonstrate that the combination of Enhertu plus pertuzumab (Perjeta) significantly outperforms the previous decade-long standard of care, THP (taxane, trastuzumab, and pertuzumab). 

  2025 Interim Results Highlights 

  • Superior Progression-Free Survival (PFS): The combination of Enhertu plus pertuzumab achieved a median PFS of 40.7 months, compared to 26.9 months for the standard THP regimen.

  • Reduced Risk: This regimen reduced the risk of disease progression or death by 44%(HR 0.56).

  • Higher Response Rates: The combination showed an objective response rate (ORR) of 85.1% and a complete response (CR) rate of 15.1%, nearly doubling the CR rate of the standard regimen (8.5%).

  • FDA Status: In 2025, the FDA granted Priority Review and Breakthrough Therapy Designation for Enhertu plus pertuzumab in this setting, with a target action date set for January 23, 2026. 

  Trial Design and Safety

  • Treatment Arms: Patients were randomized to receive Enhertu monotherapy, Enhertu plus pertuzumab, or standard THP.

  • Population: The trial enrolled 1,157 patients globally who had not received prior systemic therapy for metastatic disease.

  • Safety Profile: Adverse events were consistent with previous Enhertu trials. Interstitial Lung Disease (ILD) occurred in 12.1% of patients in the combination arm, with most cases being low-grade, though two fatal cases were reported.

  • Ongoing Monitoring: Data for the Enhertu monotherapy arm remains blinded for further analysis, and long-term overall survival (OS) data is still maturing. 

• The PATINA trial (AFT-38)

  A landmark Phase III clinical trial that has demonstrated significant benefits for patients with hormone receptor-positive (HR+), HER2-positive metastatic breast cancer. Results reported in late 2024 and early 2025 show that adding the CDK4/6 inhibitor palbociclib (Ibrance) to standard maintenance therapy dramatically slows disease progression. 

  Key Findings and Impact

  • Extended Progression-Free Survival (PFS): Patients receiving palbociclib alongside anti-HER2 therapy and endocrine therapy achieved a median PFS of 44.3 months, compared to 29.1 months for those on standard care alone.

  • Reduced Need for Chemotherapy: This combination therapy allowed many patients to delay the need for further chemotherapy by nearly four years.

  • Practice-Changing Results: Oncology experts consider these findings "practice-changing," as they provide a new, well-tolerated maintenance option that addresses resistance to standard anti-HER2 treatments.

  • Safety Profile: The side effects were consistent with the known profile of palbociclib, primarily including manageable hematologic toxicities like neutropenia. 

  Trial Overview

  • Trial ID: NCT02947685.

  • Participants: 518 patients with HR+/HER2+ metastatic breast cancer who had not progressed after initial chemotherapy.

  • Sponsorship: Conducted by Alliance Foundation Trials (AFT) with funding support from Pfizer. 

  Alternative: DIY Patina Trials

  If you are searching for "patina trials" in the context of crafting or DIY projects, it refers to testing aging solutions on various surfaces:

  • Modern Masters Patina Kits: Small kits (starting around $20–$30) allow you to test blue or green oxidizing finishes on paintable surfaces.

  • Pentart Patina Effect Set: Includes reagents and powders for creating natural-looking aged effects.

  • Paint Samples: Brands like Benjamin Moore offer "Patina" color samples (around $6) for testing interior or exterior color representation before full application. 

  This is for informational purposes only. For medical advice or diagnosis, consult a professional. AI responses may include mistakes. Learn more

  What are the side effects of palbociclib in the PATINA trial?

  What other maintenance therapies are recommended for this type of breast cancer?

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  11 sites

  • PATINA Trial Shifts Paradigm in HER2+/ER+ Breast Cancer ...

    Mar 20, 2025 — hi it's Dr kathy Miller from Indiana. University here with you today to talk about what I think was one of the most important tria...

    YouTube·Medscape

    5m

  • Palbociclib and trastuzumab for HER2-positive metastatic breast ...

    Aug 31, 2025 — Highlights * • The PATRICIA trial (cohorts A/B) evaluated palbociclib and trastuzumab in patients with HER2-positive MBC. * PAM50 ...

    ESMO Open

  • PATINA trial demonstrates benefit of palbociclib in HR+ HER2+ ...

    Dec 11, 2024 — In the study, which is sponsored by AFT, median PFS was 44.3 months (95% CI: 32.4-60.9) for patients treated with palbociclib in c...

    News-Medical

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  tem description

• DEMETHER study (NCT06172127)

  An international, multicenter, phase II clinical study evaluating a novel sequential treatment strategy for patients with previously untreated HER2-positive unresectable or metastatic breast cancer. 

  Trial Overview and Strategy

  The trial explores a "de-escalation" approach designed to maximize early treatment efficacy while reducing long-term toxicity and improving patient quality of life. 

  • Induction Phase: Patients receive 6 cycles of Trastuzumab deruxtecan (T-DXd), a potent antibody-drug conjugate typically reserved for later lines of therapy, as an initial "induction" to rapidly shrink the tumor.

  • Maintenance Phase: Following induction, patients transition to a maintenance regimen of PHESGO (a fixed-dose combination of trastuzumab and pertuzumab for subcutaneous injection). This shift aims to sustain cancer control with a more tolerable and convenient treatment.

  • Primary Objectives: The study primarily measures progression-free survival (PFS)at 1 year and overall survival (OS) at 3 years. 

  Study Details (as of 2026)

  • Status: The trial was launched in mid-2024 and is currently active at approximately 23 centers across the United States, Spain, Italy, Germany, and Brazil.

  • Participants: Aiming to enroll approximately 165 patients who have not received prior chemotherapy or HER2-targeted therapy for advanced disease.

  • Significance: By front-loading high-activity treatment (T-DXd) and moving to a chemo-free maintenance phase, researchers hope to redefine the first-line treatment standard for HER2+ metastatic breast cancer, potentially offering a more patient-centered alternative to continuous T-DXd or traditional chemotherapy combinations. 

  The trial is led by the Spanish oncology research group MEDSIR, with prominent international investigators including Dr. Javier Cortés, Dr. Hope Rugo, and Dr. Sara M. Tolaney. 

• ELEVATE trial (NCT05563220)

  The ELEVATE trial (NCT05563220) is an ongoing Phase 1b/2 open-label umbrella study evaluating the safety and efficacy of elacestrant (an oral SERD) in various oral-oral combinations for patients with ER+/HER2- metastatic breast cancer. 

  • Combinations Tested: Elacestrant is being paired with targeted agents including everolimus, abemaciclib, ribociclib, alpelisib, palbociclib, and capivasertib.

  • Key 2025 Results: Data presented at major conferences in 2025 showed that elacestrant plus abemaciclib yielded a median progression-free survival (PFS) of 14.3 months, while elacestrant plus everolimus reached 8.3 months.

  • Significance: It aims to establish elacestrant as an "endocrine backbone" that can delay the need for chemotherapy by providing effective all-oral treatment options.

• ASCENT-04 (aka KEYNOTE-D19)

  Global Phase 3 clinical trial investigating sacituzumab govitecan (Trodelvy) plus pembrolizumab (Keytruda) as an initial treatment for patients with metastatic triple-negative breast cancer (mTNBC) that expresses PD-L1. 

  Study Design

  The study included 443 patients with previously untreated, inoperable locally advanced or metastatic PD-L1–positive TNBC (defined by a Combined Positive Score [CPS] of ≥10). Patients were randomized to receive either the combination of sacituzumab govitecan and pembrolizumab or physician's choice of chemotherapy with pembrolizumab. 

  Key Findings (2025 Reports)

  The trial met its primary endpoint, demonstrating improved progression-free survival (PFS) with the combination therapy. 

  • Median PFS: 11.2 months in the experimental arm vs. 7.8 months in the control arm.

  • Risk Reduction: The combination reduced the risk of disease progression or death by 35%.
    The objective response rate (ORR) was also higher in the experimental arm (60% vs. 53%), and the duration of response (DOR) was longer (16.5 months vs. 9.2 months). Overall survival (OS) data were not yet mature, but early trends suggested a potential benefit. Quality of life data indicated a potential delay in physical decline and symptom deterioration with the combination. 

  Safety and Side Effects

  The safety profile was consistent with the known side effects of the individual drugs, with no new safety concerns. Common high-grade adverse events included neutropenia and diarrhea. Discontinuation rates due to adverse events were lower in the sacituzumab govitecan arm (12%) compared to the chemotherapy arm (31%). 

  Clinical Significance

  The ASCENT-04 results suggest that this combination could become a new first-line standard of care for patients with PD-L1–positive advanced TNBC, particularly for those who have not relapsed within 12 months after prior treatment. 

• TROPION-Breast01 (NCT05104866)

  TROPION-Breast01 (NCT05104866)

   is a global, Phase 3 trial assessing the efficacy and safety of datopotamab deruxtecan (Dato-DXd) against standard chemotherapy in patients with HR+/HER2- metastatic breast cancer. More details about the trial's design and target population can be found on ScienceDirect. 

  Clinical Outcomes & Regulatory Status

  • PFS Success: The trial met its primary endpoint of PFS, demonstrating a statistically significant and clinically meaningful improvement with Dato-DXd (Hazard Ratio: 0.63), consistent across subgroups.

  • OS Result: The final OS analysis did not reach statistical significance.

  • Safety Profile: Dato-DXd showed a manageable safety profile with fewer grade 3 or higher treatment-related adverse events compared to chemotherapy. Common side effects included nausea and stomatitis.

  • FDA Approval: Based on the results, the FDA approved datopotamab deruxtecanon January 20, 2025, for treating patients with unresectable or metastatic HR+/HER2- breast cancer.