📬 Breast Cancer Intelligence Digest — Week 2026-W35

CompassHER2-pCR reports a 43.8% pCR rate with neoadjuvant THP, tissue-free ctDNA proves strongly prognostic in early TNBC, and NeoZanHER, CAPItello-291 PTEN IHC, TROPION-Breast02 and multiple FDA/EC actions fill out the week.

⚡ TL;DR

📄 Publications

Ovarian reserve as a measure of adjuvant chemotherapy benefit in hormone receptor positive (HR-positive), HER2-negative, node-positive breast cancer in SWOG S1007 (RxPONDER). — AMH >=10 pg/ml showed significant interaction with chemotherapy benefit for IDFS (Padj = 0.0034)

🐦 Twitter / 🦋 Bluesky

Real-world post-T-DXd sequencing: switching chemotherapy mechanism of action is what works — A real-world analysis of post-T-DXd regimens in metastatic breast cancer found the best activity came from switching the mechanism of action of the chemotherapy
CompassHER2-pCR published: 43.8% pCR with four cycles of THP, and weekly paclitaxel beats q3w docetaxel — Four cycles of THP produced pCR in 44% of patients with HER2+ early breast cancer, with higher chance if ER <=70% and HER2 3+, weekly paclitaxel better than q3w docetaxel, and HER2DX associated with pCR
CDK inhibitors past CDK4/6: a Nature Reviews Drug Discovery review on CDK2 and next-generation selective agents — CDK4/6 inhibitors transformed breast cancer but resistance remains key, with CDK2 inhibition proposed for refractory disease and HER2/PI3K combinations plus next-generation selective CDK4 inhibitors broadening options
AI-based TIL scoring in early HER2+ breast cancer (NSABP B-41) tracks with pCR across ER subtypes — AI-based TIL assessment was associated with pCR across ER subtypes in early HER2-positive breast cancer and may complement manual TIL scoring
NeoZanHER: chemotherapy-free neoadjuvant zanidatamab yields 30% pCR in small node-negative HER2+ tumors, all in IHC 3+ disease — Among 20 patients with 1-3 cm N0 tumors, pCR was 30% overall and 40% in IHC 3+, pCR/RCB-1 was 50%, with no grade >=3 TRAEs and no pCR in IHC 2+/ISH+ disease

Full details below ↓

📄 What's Being Published

Manuscripts:

Ovarian reserve as a measure of adjuvant chemotherapy benefit in hormone receptor positive (HR-positive), HER2-negative, node-positive breast cancer in SWOG S1007 (RxPONDER). — Kalinsky K et al., Ann Oncol

Pretreatment AMH and other hormones were assessed in a blinded fashion from 1,556 participants aged <55 years. AMH ≥10 pg/ml showed significant interaction with chemotherapy benefit for IDFS (Padj = 0.0034): in the 64% of women with AMH ≥10 pg/ml, IDFS was superior with CET compared with ET alone (HR 0.46, 95% CI 0.33–0.65, Padj = 0.00012), whereas the 36% with AMH <10 pg/ml derived no benefit (HR 1.27, 95% CI 0.81–1.99, Padj = 0.47). Baseline estradiol, progesterone, LH, and FSH were not predictive of CET benefit.

Clinical bottom line: Baseline AMH — not age or menopausal status — should be the measure used to decide whether a premenopausal patient with RS≤25 node-positive disease gains from adding chemotherapy to endocrine therapy.

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Pathologic Complete Response (pCR) Rate and Predictors of Response to Taxane, Trastuzumab, and Pertuzumab in HER2‑Positive Breast Cancer: Secondary Analyses of EA1181/CompassHER2 pCR. — Tung Nadine et al., J Clin Oncol

A total of 2,175 patients were enrolled (781 HER2+/ER−; 1,394 HER2+/ER+); of 2,141 who initiated THP, the overall pCR rate was 43.8%, with rates of 63.7% in HER2+/ER− and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, PR-negative or low expressing, HER2 IHC 3+, and in patients treated with once per week paclitaxel. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates after adjustment for clinicopathologic variables.

Clinical bottom line: Neoadjuvant THP without chemotherapy escalation clears nearly two-thirds of HER2+/ER− tumors; low hormone receptor expression, HER2 IHC 3+, weekly paclitaxel, and a high HER2DX score should be used to select which patients receive this de-escalated backbone.

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🗂 Every paper considered this week, including the ones that didn’t make it →

🗣️ What People Were Discussing This Week

How these are chosen: filtered for clinical relevance, grouped by the new development discussed, then ordered by engagement (bookmarks and reposts).

Real-world post-T-DXd sequencing: switching chemotherapy mechanism of action is what works

A real-world analysis of post-T-DXd regimens in metastatic breast cancer found that the best activity came from switching the mechanism of action of the chemotherapy. One framing circulating among oncologists calls for sorting ADCs by payload rather than target: sacituzumab, different target from T-DXd but same payload, failed right after it, while T-DM1, same target but different payload, still worked. Beyond target loss, HER2-ADC resistance mechanisms include impaired internalization and trafficking, lysosomal processing, payload sensitivity, and stromal barriers, with losartan identified as enhancing HER2-ADC activity in preclinical models. The central debate is whether ADC sequencing decisions after T-DXd should be driven by payload class rather than antigen target.

Discussed by: @OncBrothers, @OncBrothers, @stolaney1

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CompassHER2-pCR published: 43.8% pCR with four cycles of THP, and weekly paclitaxel beats q3w docetaxel

The EA1181/CompassHER2 pCR trial reports that of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER− and 32.4% in HER2+/ER+ tumors, with weekly paclitaxel outperforming q3w docetaxel and HER2DX score associated with pCR. Oncologists note that higher pCR probability in patients with ER ≤70% and HER2 IHC 3+ sharpens the selection argument for this de-escalated regimen. Simultaneously, clinicians are weighing underlying tumor biology alongside tumor size when deciding the neoadjuvant approach in early HER2+ disease. The open question is which early HER2+ patients still require an anthracycline or an ADC up front given the 43.8% pCR rate from THP alone.

Discussed by: @kazuki_nozawa, @stolaney1, @stolaney1

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CDK inhibitors past CDK4/6: a Nature Reviews Drug Discovery review on CDK2 and next-generation selective agents

A Nature Reviews Drug Discovery review frames CDK4/6 inhibitors as having transformed breast cancer treatment while resistance remains the key limiting factor; CDK2 inhibition is proposed as a strategy for refractory disease, with HER2/PI3K combinations and next-generation selective CDK4 inhibitors broadening available options. On the guideline front, updated NCCN guidelines have added gedatolisib plus fulvestrant, with or without palbociclib, for pretreated PIK3CA wild-type advanced breast cancer. The debate centers on whether CDK2 is the next actionable node after CDK4/6 progression or whether PI3K-pathway combinations will dominate post-progression therapy.

Discussed by: @OncoAlert, @OncLive

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AI-based TIL scoring in early HER2+ breast cancer (NSABP B-41) tracks with pCR across ER subtypes

In early HER2-positive breast cancer (NSABP B-41), AI-based TIL assessment was associated with pCR across ER subtypes and may complement manual TIL scoring. In a separate retrospective cohort of 289 women with triple-negative breast cancer, IHC-defined molecular subtypes varied substantially across clinical trajectories, with higher stromal TILs independently associated with improved overall survival in early-stage disease but not in metastatic disease. Whether AI-read TIL scoring is ready to replace manual pathologist scoring as the reproducible immune biomarker in HER2+ neoadjuvant trials remains an open question among specialists.

Discussed by: @DFCI_BreastOnc, @OncoAlert

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NeoZanHER: chemotherapy-free neoadjuvant zanidatamab yields 30% pCR in small node-negative HER2+ tumors, all in IHC 3+ disease

Among 20 patients with 1–3 cm, N0 tumors treated with single-agent zanidatamab, pCR was 30% overall and 40% in HER2 IHC 3+ (6/15 patients), pCR/RCB-1 reached 50%, there were no grade ≥3 treatment-related adverse events, and no pCR was observed in the 5 IHC 2+/ISH+ patients. All patients achieving pCR had HER2 IHC 3+, ERBB2 amplification, and PAM50 HER2-enriched disease. As a comparator, PHERGain-2 selected 396 patients with 5–30 mm, N0, centrally confirmed IHC 3+ tumors, and eight cycles of HP ± endocrine therapy produced a 59.6% pCR rate, posing a direct question about whether zanidatamab monotherapy adds anything in this biomarker-selected population.

Discussed by: @kazuki_nozawa, @OncoAlert

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CAPItello-291 exploratory analysis: PTEN IHC finds capivasertib responders that NGS misses

In the CAPItello-291 exploratory analysis, PTEN was deficient by IHC in 19.1% of tumors, with overall IHC versus NGS agreement at 87%; among PTEN-deficient tumors, mPFS was 9.3 versus 3.7 months with HR 0.52 favoring capivasertib. Critically, among PTEN-deficient tumors without PIK3CA/AKT1/PTEN alterations detected by NGS, mPFS was 16.2 versus 4.6 months (HR 0.43, 95% CI 0.15–1.05), identifying a population that NGS alone would exclude. International experts have separately published recommendations on biomarker testing in advanced/metastatic HR+/HER2− breast cancer to support treatment decision-making, adding context to the question of whether PTEN IHC should be added alongside NGS before ruling a patient out of capivasertib eligibility.

Discussed by: @JaniceTNBCmets, @LinglingTian123

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SERENA-6 update in Lancet Oncology reopens the debate on switching at ESR1 emergence before progression

A new update in The Lancet Oncology from the SERENA-6 trial examines switching to camizestrant at ESR1 mutation emergence before disease progression during first-line treatment of hormone receptor-positive advanced breast cancer. Oncologists are debating whether to execute an early switch to oral SERDs as soon as an ESR1 mutation emerges in the absence of radiographic progression, with specialists making the case for an early ctDNA-guided switch to camizestrant in HR-positive breast cancer. The central question is whether serial ctDNA monitoring for ESR1 emergence is worth implementing before overall survival data from SERENA-6 are available.

Discussed by: @DFCI_BreastOnc, @DFCI_BreastOnc, @OncLive

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TROPION-Breast01 safety and patient-reported outcomes published in ESMO Open

Safety and patient-reported outcomes from the phase III TROPION-Breast01 study of datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic HR+/HER2− breast cancer were published in ESMO Open. Clinicians read the data as Dato-DXd pairing meaningful disease control with delayed quality-of-life deterioration, supporting a post-chemotherapy ADC role while calling for proactive toxicity management. The debate is whether delayed quality-of-life deterioration data change where Dato-DXd sits relative to single-agent chemotherapy in pretreated HR+/HER2− disease.

Discussed by: @DFCI_BreastOnc, @Dr_Oncologista

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PRO B randomized trial: alert-based ePRO monitoring lowers fatigue in metastatic breast cancer

The PRO B randomized trial showed that alert-based digital patient-reported outcome monitoring was associated with lower fatigue at 6 months versus usual care, with improvement exceeding the minimal clinically important difference; specifically, ePRO monitoring reduced fatigue by 5.4 T-score points and improved physical functioning. The trial enrolled patients with metastatic breast cancer and represents the first randomized evidence that structured digital symptom monitoring produces a clinically meaningful fatigue benefit. Whether alert-based ePRO monitoring should be funded as standard supportive care in metastatic breast cancer clinics is the question clinicians are now working through.

Discussed by: @EladSharonMD, @Dr_Oncologista

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TROPION-Breast02: Dato-DXd improves PFS and OS in first-line advanced TNBC when immunotherapy is not an option

In the phase III TROPION-Breast02 trial of 644 patients with advanced TNBC where immunotherapy was not an option, Dato-DXd versus investigator-choice chemotherapy produced PFS of 10.8 versus 5.6 months (HR 0.57), OS of 23.7 versus 18.7 months (HR 0.79), ORR of 63% versus 29%, and duration of response of 12.3 versus 7.1 months. The European Commission approved Dato-DXd monotherapy for first-line metastatic TNBC, providing a new option in this setting. Oncologists are debating whether "immunotherapy not an option" defines a broad enough first-line TNBC population to establish Dato-DXd as a new standard or whether it constitutes a niche indication.

Discussed by: @ChandrakanthMv, @OncLive, @CancerTodayMag

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Vepdegestrant approved: the first PROTAC degrader enters ER+/HER2- advanced breast cancer

Vepdegestrant, the first PROTAC protein degrader, is now approved for ER+/HER2− advanced breast cancer; in ESR1-mutant disease it doubled PFS versus fulvestrant (5 vs 2.1 months). In parallel, oncologists are working through combination questions for oral SERDs with CDK4/6 inhibitors or PAM pathway agents in HR+/HER2− metastatic disease. The positioning debate is where vepdegestrant sits against the established oral SERDs given the 5 versus 2.1 month PFS gain over fulvestrant in ESR1-mutant disease.

Discussed by: @ClinOncNews, @DFCI_BreastOnc

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FDA approves palbociclib with trastuzumab and endocrine therapy in HR+/HER2+ advanced disease on PATINA

The FDA approved palbociclib with trastuzumab, with or without pertuzumab, plus endocrine therapy for HR+/HER2+ locally advanced or metastatic breast cancer based on the PATINA trial. Clinicians are simultaneously discussing how recently FDA-approved ADCs for breast cancer will affect practice alongside this CDK4/6 inhibitor approval in the HER2+ setting. The question now being worked through is whether adding a CDK4/6 inhibitor to HER2-directed maintenance becomes the default in HR+/HER2+ metastatic disease following PATINA's approval.

Discussed by: @eaonc, @OncLive

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🔥 Top Ranked Tweets

Sara Tolaney @stolaney1

RT @KolPulseAI: DESTINY-Breast09 (NCT04784715): T-DXd (Enhertu) + pertuzumab vs THP, 1L HER2+ mBC. mPFS 40.7 vs 26.9 mo, HR 0.56. FDA approved Dec 15, 2025. 2-min KOL recap: @stolaney1 @PTarantinoMD @DrSGraff @ErikaHamilton9 @AstraZeneca @DaiichiSankyo https://t.co/20LVQZXcaX https://t.co/3ScDkfdtM2

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