Day One: International Summit on Breast Cancer

For years we have asked whether a node-positive woman with ER-positive disease truly needs chemotherapy. Professor Giuseppe Curigliano opened his ASCO read-out with the abstract he and Professor Hope Rugo judged the most important of the meeting: OPTIMA. The trial used a 50-gene test to decide, and the answer it gave is more complicated than the headline suggests.

Curigliano walks through the year's HR-positive, HER2-negative data with a clinician's discipline: what the trial actually showed, where the numbers are solid, and where he is not yet willing to change practice. OPTIMA anchors the talk, followed by fast, honest updates across the early and metastatic settings, including one closely watched trial that missed its endpoint.

Key points for clinicians:

• OPTIMA randomized 4,420 patients and used the Prosigna 50-gene (PAM50) test to direct chemotherapy in node-positive HR-positive, HER2-negative disease. Invasive breast cancer-free survival events were nearly identical between arms, 7.2 percent in the control arm and 7.3 percent in the test-directed arm, meeting non-inferiority. The authors concluded the test identifies a group with minimal chemotherapy benefit, at most two recurrences prevented per 100 patients.

• Curigliano's caution is the point worth keeping: only 18 percent of OPTIMA patients had four to nine involved nodes, so he is not yet confident omitting chemotherapy in that group, and an academic trial incorporating CDK4/6 inhibitors is ongoing.

• NATALEE, with longer follow-up, confirmed ribociclib's invasive disease-free survival benefit. A PAM50 analysis suggested the benefit extends across intrinsic subtypes, including HER2-enriched and basal-like, pointing to potential predictive value.

• In advanced disease, the evERA data showed giredestrant plus everolimus delaying progression and chemotherapy in both ESR1-mutant and non-mutant patients, with an early overall survival trend.

• VICTORIA-1 nearly doubled median progression-free survival in PIK3CA-mutant disease, from 5.6 to 11.1 months, with the gedatolisib, palbociclib and fulvestrant triplet, and stomatitis around 16 percent managed with prophylactic mouthwash.

• persevERA, the first oral SERD trial in an endocrine-sensitive first-line metastatic population, did not meet its primary endpoint. Median progression-free survival was 33 months with giredestrant plus palbociclib versus 28 months with letrozole plus palbociclib, a hazard ratio of 0.89 that was not statistically significant. Curigliano ties the result to the endocrine-sensitive, largely ESR1 wild-type population enrolled. He closed with OASIS-4, where elinzanetant improved quality of life by controlling vasomotor symptoms during endocrine therapy.

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.

Triple negative breast cancer used to be the subtype with the fewest moves. In this ASCO 2026 read-out, Professor Hope Rugo makes the case that the field now has too many good options and not enough answers about how to sequence them.

Professor Rugo walks through the practice-changing and practice-shaping data across the neoadjuvant and metastatic settings. She starts with the long-term KEYNOTE-522 follow-up, moves through trials that try to prime the immune response and drop anthracyclines, and then turns to the antibody-drug conjugates that are reshaping first-line metastatic care. Her recurring theme is that biology and order now matter as much as the agents themselves, and that the era of a chemotherapy-only control arm in higher-risk disease is over.

Key points for clinicians:

• KEYNOTE-522 at 7.8 years of median follow-up sustains the event-free and overall survival benefit of adding pembrolizumab, with the largest gains in patients who did not achieve pCR and a shift toward lower residual cancer burden. PD-L1 predicts chemotherapy sensitivity, not pembrolizumab benefit.

• The TRAD phase 2 trial used radiation plus pembrolizumab as induction and increased T-cell infiltration and pCR, supporting the idea of turning cold tumors hot.

• HELEN-011 showed camrelizumab added to a non-anthracycline docetaxel-carboplatin backbone improves pCR regardless of PD-L1 status, reinforcing that immunotherapy-free control arms no longer belong in T2 or node-positive TNBC.

• In I-SPY 2.2, four doses of rilvegostomig, an anti-PD-1/TIGIT bispecific, plus T-DXd produced a 72 percent pCR rate overall, with 62 percent of responders reaching pCR chemotherapy-free and 97 percent without anthracyclines, a model for response-adaptive de-escalation.
  

In metastatic disease, ASCENT-04 positions sacituzumab govitecan plus pembrolizumab as a potential new first-line standard for untreated PD-L1-positive TNBC, while ASCENT-03 and TROPION-Breast02 extend the case for TROP2 ADCs, and PFS2 signals across trials suggest treatment order matters.

• Among newer agents, the HER2xEGFR bispecific izalontamab showed a striking PFS hazard ratio of 0.29 and improved overall survival in pretreated disease, with cytopenias that will require careful management.

Most of what we know about the genomics of breast cancer was written from Western cohorts. Professor Ning Liao spent seven years asking whether it holds in Chinese patients, and where it does not, the differences change how we treat.

Drawing on more than a decade of next-generation sequencing at Guangdong Provincial People's Hospital, Professor Liao maps the somatic and germline landscape of breast cancer in a Chinese population and sets it against the Western reference. The picture that emerges is not a smaller version of the same disease. It is a different distribution of drivers, and that has direct consequences for testing, for targeted therapy, and for how we read a patient's risk.

Key points for clinicians:

• In this cohort, the most frequently mutated somatic gene is TP53 at 45 percent, followed by PIK3CA at 44 percent and HER2 amplification or mutation at 24 percent, each higher than reported Western rates.

• The leading germline finding is BRCA2 at 3.44 percent rather than BRCA1 at 2.10 percent, a reversal of the usual expectation, with PALB2, CDH1, and RAD51C following.

• ESR1 mutation runs near 1 percent in primary disease and rises to 18.6 percent in metastatic disease, a marker of acquired endocrine resistance worth tracking.

• HER2 focal versus broad amplification, and HER2 copy number, help predict response to neoadjuvant anti-HER2 therapy, including antibody-drug conjugates.

• A weekly international Molecular Tumor Board, now in its seventh year, turns these findings into individual treatment plans.

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.
  

For fifty years, a positive lymph node meant the whole axilla came out. Dr. Isabel Rubio's read of the AXANA registry closes that chapter for a large group of patients. When a clinically positive axilla becomes cancer-free after neoadjuvant treatment, a full axillary lymph node dissection adds nothing to three-year recurrence control, and it takes away the lymphedema.

Rubio walks through how neoadjuvant treatment has reshaped both breast and axillary surgery, and where the field goes next. On the breast, she makes the case that a breast pathologic complete response is not required for breast-conserving surgery, and that intraoperative ultrasound is delivering higher negative-margin rates and better cosmetic outcomes. On the axilla, she traces the path from routine dissection in the 1970s, to sentinel node biopsy in the 1990s, to today's targeted approaches, and lays out the prospective data that now support doing less. She closes on the real frontier: omitting sentinel node biopsy, and even surgery itself, in excellent responders, with genomic profiling beginning to stand in for surgical staging.

Key points for clinicians:

• A breast pathologic complete response is not a prerequisite for breast-conserving surgery. In the AXANA prospective registry, real-world 2020 data show roughly two-thirds of neoadjuvant patients undergoing breast conservation, with intraoperative ultrasound raising negative-margin rates and improving cosmesis.

• Targeted approaches now sit alongside sentinel node biopsy and axillary dissection. For the targeted axillary dissection and targeted lymph node biopsy, using clips, black ink, or magnetic or radioactive seeds, the false negative rate is below 5 percent in the majority of series.

• In AXANA, patients with a clinically positive axilla who achieve a complete pathologic response in the axilla show no significant difference in three-year axillary recurrence-free survival whether they undergo axillary dissection or a sentinel node biopsy or TAD procedure. - This confirms the retrospective data, and it removes the lymphedema burden of dissection.
  

In more than 5,000 AXANA patients presented at ASCO, tumor biology predicted axillary response, not nodal burden. Higher axillary pathologic complete response tracked with Ki-67 above 20 percent, triple negative and HER2-positive disease, and higher grade. The initial number of suspicious nodes was not associated with response, which should settle the three-versus-four-node debate.

• On radiation, NSABP B-51 (nearly 2,000 patients, five-year follow-up) found that regional nodal irradiation did not improve recurrence-free interval or disease-free survival in patients with a clinically positive axilla who reached a pathologic complete response. Rubio notes the caveats her radiation oncology colleagues raise: short follow-up and a possible triple negative signal.

• The next step is omission. MD Anderson's Kuerer work reported no ipsilateral breast recurrences at five years in highly selected HER2-positive and triple negative responders, and trials including EUBREAST, ASLAN, and OPTIMIST are testing omission of sentinel node biopsy. By 2030, a defined group of excellent responders may safely skip surgical staging altogether.

In eight-year data on small, favorable tumors, endocrine therapy alone left a 16 percent recurrence rate, radiation alone 9 percent, and the two together about 3 percent. Survival was the same in all three groups. Dr. Suzanne Klimberg opened there to make the uncomfortable point plainly: most women with favorable breast cancers gain little from whole breast radiation, and we still give it to nearly all of them.

Her talk asks whether we can finish local treatment in the operating room instead. Klimberg walks through the trials that already point toward de-escalation, then presents her own alternative to radiation: intraoperative cavitary radiofrequency ablation, done at the time of lumpectomy. She lays out the preclinical work, the single-institution ABLATE-1 experience, a published seven-site phase 2 trial in 242 patients, and a new surgeon-friendly device now heading into an Alliance Cooperative Group trial. The through-line is a practical one for anyone who treats early breast cancer: match the intensity of local therapy to the small group who truly need it, and spare the rest the cost, the toxicity, and the trips they often cannot make.

Key points for clinicians:

• In small favorable tumors, radiation lowers local recurrence but not survival, so the clinical question is not whether it works but how to identify the few patients who benefit. Trials like the Canadian and PRIME data show good local control in selected older women, and IDEA-type work found roughly 100 percent breast cancer survival with endocrine therapy alone at recurrence scores under 18. The DEBRA trial (NRG-BR007) is now randomizing endocrine therapy plus radiation against endocrine therapy alone in HER2-negative tumors stratified by oncotype under 11 and 11 to 18.

• Radiation carries real access and toxicity costs. Klimberg notes that fewer than 80 percent of patients in parts of the rural United States complete their full prescribed dose, and that some women choose mastectomy simply because they cannot return daily for treatment.

• The proposed alternative is intraoperative radiofrequency ablation of the lumpectomy cavity, producing about a one centimeter concentric ablation zone, validated on mastectomy and resection specimens and monitored in real time with Doppler. It adds roughly 15 to 20 minutes and can ablate residual disease at focally positive margins, reducing the need to return for re-excision.

• In ABLATE-1 (100 patients, single institution), two thirds of patients with positive margins avoided re-excision and two thirds of the full cohort avoided radiation entirely, with low complications, less pain, and good cosmesis.

• In the published seven-site phase 2 trial (242 patients, risk-adjusted so node-positive and aggressive disease still received whole breast radiation), the mastectomy rate was 2.8 percent, re-excision for positive margins under 5 percent, and local recurrence 2.6 percent. About 80 percent of patients avoided radiation. Breast pain at 6 to 12 months was 19 percent in the irradiated group versus 1.7 percent with ablation alone, roughly fivefold less, with good to excellent cosmesis in almost 90 percent.

• A new device that plugs into the existing Bovie unit makes the technique faster to learn and available even in rural operating rooms. A first report covered 55 ablations in 44 women, and the FDA has asked for a small additional cohort before the Alliance trial.

A 34-year-old woman finishes treatment, interrupts her endocrine therapy to try for a baby, and two years later still cannot get pregnant. Dr. Hee Jeong Kim opened with that case because it is the one too many clinics reach only after the window has closed. Her argument is simple and hard to ignore: the conversation about fertility has to start on the day of diagnosis, not years into treatment.

Dr. Kim, a breast surgeon at Asan Medical Center speaking on behalf of the Korean Breast Cancer Society, lays out why young women are a distinct clinical population and what it takes to protect both their survival and their chance at a family. Young women under 45 make up about 19 percent of breast cancer worldwide and roughly 30 percent in the Korean registry, and they have historically carried worse survival. Adding ovarian function suppression to endocrine therapy has narrowed that gap, but longer and more intensive treatment collides with the years these women would be building families. The talk moves from that tension to concrete practice: fertility preservation before treatment, ovarian function suppression during chemotherapy, safe interruption of endocrine therapy, and the real-world barriers that keep good options from ever being offered.

Key points for clinicians:

• Young women under 45 are about 19 percent of breast cancer cases worldwide and about 30 percent in the Korean breast cancer registry, with historically higher mortality on SEER data. Because amenorrhea is associated with improved survival, ovarian function suppression added to tamoxifen (studied since 2003 in Europe and 2009 in Korea) has consistently shown a survival benefit.

• Breast cancer survivors report a 60 percent lower chance of getting pregnant, driven by chemotherapy, extended endocrine therapy, and fear of recurrence. Yet in the POSITIVE trial population, 36 percent of young patients reported interest in pregnancy within five years of diagnosis.

• The POSITIVE trial showed that interrupting endocrine therapy after two to three years to attempt pregnancy did not compromise safety, and that fertility preservation at the time of diagnosis raised the pregnancy rate roughly 2.4 times. The practice lesson is to start fertility and pregnancy counseling at diagnosis, not later.

• Ovarian function suppression given concurrently with chemotherapy roughly doubled ovarian preservation and pregnancy rates versus controls, without a survival penalty. Random-start ovarian stimulation with an aromatase inhibitor to limit estrogen exposure, followed by a GnRH agonist, allows egg retrieval without delaying chemotherapy.

• The barriers are as much systemic as biological. In a US survey of oncologists willing to enroll patients on these trials, more than half still felt uncomfortable recommending that women stop endocrine therapy, and across Asian and Latin American surveys the top barriers were time constraints, no referral system, treatment delay, and cost. Among BRCA carriers, the 10-year pregnancy rate was 22 percent in one series and only 10 percent at Asan, partly because prenatal diagnosis is not permitted in Korea.

• Dr. Kim's myBC study, a shared-decision-making program for young women with breast cancer, has enrolled 11,000 patients prospectively plus 5,500 retrospectively, using decision aids, patient-partner research, and even a metaverse symposium for women who cannot easily leave work. It has since expanded into myHOP for young people with all cancers, reframing the goal as life course oncology: fertility, pregnancy, parenting, survivorship, and return to work as one continuous journey.

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.