Day One: International Summit on Breast Cancer

The story of the year in HER2-positive breast cancer is a single class of drug. Dr. William Gradishar walked through it plainly: antibody drug conjugates, and trastuzumab deruxtecan in particular, are now moving earlier in treatment, from metastatic disease into the operating room and beyond. The question is no longer whether they work. It is who needs them, and at what cost.

Gradishar traced trastuzumab deruxtecan across the full arc of the disease, from high-risk residual disease after surgery, to neoadjuvant therapy, to first-line metastatic care. He was careful about the parts that are still open. The efficacy is real and the numbers are large, but event-free survival in the early-stage trials is immature, the lung toxicity is uncommon but serious, and optimizing endocrine therapy alongside these agents remains unresolved. He closed with a candid look inside the NCCN process, showing how the panel debates and votes before a trial result becomes a guideline.

Key points for clinicians:

• In DESTINY-Breast05, patients with high-risk residual disease after neoadjuvant HER2-directed therapy were randomized to trastuzumab deruxtecan or T-DM1 for 14 cycles. Trastuzumab deruxtecan produced an additional absolute reduction of about 9 percent in recurrence, a further 50 percent reduction in the odds of an event, with the benefit concentrated in distant recurrence and a hint of CNS activity.

• Interstitial lung disease remains the toxicity that matters most. In DESTINY-Breast05 data presented by Michael Lynch, most drug-related ILD was low grade and did not differ between concurrent and sequential radiation. Severe events and second events after rechallenge were rare, but a small number of patients can have a very severe outcome, so vigilance stays essential in the curative setting.

• Neoadjuvantly, the NeoCARH read-out showed carboplatin added nothing to a THP backbone. The pCR rate was identical with or without it, in both ER-positive and ER-negative disease, so THP is likely sufficient.

• In DESTINY-Breast11, trastuzumab deruxtecan followed by THP improved the pCR rate by an absolute 11 percent over AC-THP, across ER-positive and ER-negative patients, with more patients reaching RCB 0 to 1. The dedicated single-agent arm was stopped by the IDMC for lower pCR, and event-free survival is not yet mature.

• In first-line metastatic disease, DESTINY-Breast09 showed trastuzumab deruxtecan plus pertuzumab extended PFS from 26 to 40 months versus the Cleopatra THP regimen, raised the objective response rate from 78 to 85 percent, and doubled complete responses from 8 to 15 percent, with patient-reported outcomes comparable between arms.

• The competing strategies are worth knowing. HER2CLIMB-05 added tucatinib as maintenance and raised EFS from 16 to 24 months, with the larger benefit in hormone receptor negative disease, while PATINA extended PFS from 26 to 44 months in ER-positive patients by adding a CDK4/6 inhibitor to endocrine therapy. Because trastuzumab deruxtecan cannot be combined with a CDK4/6 inhibitor, sequencing in HER2-positive, ER-positive disease is still being worked out.

The through-line for prevention and earlier detection: the largest gains here come from treating disease before it becomes metastatic, and from bringing the most effective agents forward to the residual-disease and neoadjuvant settings. Catching high-risk disease early, and matching the right patient to the right regimen, is where the next reduction in recurrence and CNS relapse will come from.

A PI3 kinase mutation is either there or it isn't. An ESR1 mutation is different. It is rare at first diagnosis and shows up later, under the pressure of endocrine therapy. Dr. William Gradishar's point is blunt: a negative ESR1 test today does not stay negative, and if you stop looking you cannot use the drugs that now exist to treat it.

Gradishar walks through the resistance problem in hormone receptor positive, HER2 negative metastatic breast cancer and the wave of oral estrogen receptor degraders built to answer it. After a CD4/6 inhibitor, the fraction of patients carrying an ESR1 mutation roughly triples to about 30 percent, and across lines of therapy some series put it near 40 percent. He reads out the trials that now define practice, elacestrant, imlunestrant, vepdegestrant, camizestrant and giredestrant, and he is honest about their limits: the survival curves separate, but every one of them shows the same steep early drop-off from de novo resistant disease that no current drug is reaching. He closes on the hardest open question in the field, whether acting on a molecular signal before imaging progresses actually changes the disease, and on the FDA and European regulators splitting on that exact question.

Key points for clinicians:

• ESR1 mutations are the most common acquired resistance mechanism in HR positive metastatic disease. They are infrequent in a newly diagnosed primary tumor but emerge under endocrine therapy, tripling to roughly 30 percent after a CD4/6 inhibitor, with some series reaching 40 percent across later lines. RB abnormalities account for up to 10 percent.

• Because these mutations appear over time, a single biomarker test is not enough. NCCN, ESMO and ASCO all call for biomarker analysis by ctDNA or tissue, and a mutation absent at first evaluation can appear later, so repeat testing is the practical takeaway.

• The new oral degraders share a rationale: higher potency than fulvestrant, oral dosing, and activity in ESR1-mutant and post-CD4/6 patients. Elacestrant (EMERALD) improved PFS over standard endocrine therapy, with a larger benefit the longer a patient had stayed on a prior CD4/6 inhibitor, a possible surrogate for endocrine sensitivity.

• Imlunestrant (EMBER-3) as monotherapy beat standard endocrine therapy only in ESR1-mutant patients, by roughly one and a half to two months. Combined with abemaciclib it helped regardless of ESR1 status and softened the early drop-off, at the cost of the expected GI toxicity from abemaciclib.

• Vepdegestrant (VERITAC-2), a PROTAC that routes the estrogen receptor to proteasomal degradation, roughly doubled PFS versus fulvestrant, from about two months to just above five, with 43 percent of patients ESR1-mutant.

• The unresolved question is early molecular switching. SERENA-6 switched patients to camizestrant on ctDNA-detected ESR1 emergence before any imaging progression and reported 16 months PFS versus 9. Gradishar, who sat on the ODAC panel, notes the FDA voted 6 to 3 against approval over trial design, while the European agency gave a positive opinion, and he cautions that PADA-1 earlier showed an apparent switching benefit that washed out downstream.
  

The most useful thing about a tumor board is watching experts disagree in good faith. In this session, an international panel takes two early-stage breast cancer cases and works them the way a real team would, out loud, with the tension left in.

Moderated by Professor William Gradishar, the panel walks a 35-year-old with BRCA1-associated triple-negative breast cancer and a 50-year-old with HER2-positive, hormone-receptor-positive breast cancer from diagnosis through surgery, systemic therapy, and the decisions in between. What comes through is how much thoughtful practice varies across the United States, Europe, and Asia, and how often the right answer is a shared decision rather than a protocol.

Key points for clinicians:

• Case 1 covers nodal clipping, neoadjuvant KEYNOTE-522 chemoimmunotherapy, PARP inhibition for BRCA carriers, and de-escalation of axillary surgery after an excellent response.

• Fertility preservation is treated as part of the plan, with egg or embryo harvesting and GnRH agonists during chemotherapy in a young patient.

• The panel openly disagrees on prophylactic bilateral mastectomy in a BRCA1 carrier, weighing contralateral risk against the limits of the survival evidence.

• Case 2 examines neoadjuvant therapy thresholds for HER2-positive disease, THP versus more intensive regimens, and where antibody-drug conjugates such as T-DXd are indicated before or after after surgery.

• Regional differences in mastectomy rates and de-escalation, across the US, South Korea, and China, show how the same case is managed differently around the world.