Breast Cancer’s Fastest-Moving Questions: Which Expert Recommendations Have Held Up?

Breast Cancer’s Fastest-Moving Questions

In November 2024, a group of breast cancer specialists convened to work through clinical questions that guidelines do not fully answer, and gray areas that oncologists navigate without level 1 evidence. This meeting was part of Bridging the Gaps (BTG), an annual initiative in which US-based experts address management questions for which level 1 evidence is lacking, using a modified Delphi consensus process to develop expert recommendations. Discussion spanned HER2-directed therapy in early disease, estrogen receptor (ER)–targeting strategies, immunotherapy in triple-negative disease, and the expanding role of antibody-drug conjugates (ADCs). Breast cancer therapeutics advance so quickly that a year-old snapshot is, in places, already a snapshot of the past. Below are 4 areas where that guidance holds up or has already been overtaken by new approvals.This article sets the stage for the next BTG Breast Cancer meeting, planned for November 2026, which will take up where this discussion left off.

ER Targeting: A Widening Tool Kit

CDK4/6 inhibitors combined with endocrine therapy remain the first-line backbone for HR+/HER2-negative metastatic disease; ribociclib is the only agent in the class with a demonstrated overall survival (OS) benefit over endocrine therapy alone (63.9 vs 51.4 months).¹ In practice, agent selection is individualized, although no randomized trial has directly compared agents within the CDK4/6 inhibitor class. Goetz et al noted a numerical but not statistically significant OS improvement with abemaciclib in the visceral-disease subgroup.² For patients progressing on a CDK4/6 inhibitor plus endocrine therapy, guidance favors testing for PIK3CA/AKT1/PTEN alterations to inform use of capivasertib plus fulvestrant.^3,4 For ESR1-mutated disease progressing on that backbone, oral selective estrogen receptor degraders (SERDs) were identified as the most promising next step, although elacestrant was, at the time, the only approved SERD.⁵ That has since changed; imlunestrant was FDA-approved in September 2025, allowing fora second oral SERD option.^6,7 Vepdegestrant, an oral ER-degrading proteolysis-targeting chimera, was added to NCCN guidelines as a category 2A option in May 2026⁸ and is now FDA-approved based on results from the VERITAC-2 trial (NCT05654623).⁹ Camizestrant’s path has been more challenging; in April 2026, an FDA advisory committee voted that additional risk-benefit data are needed before approval, and a decision remains pending, although the same regimen has already been approved in the European Union and other markets.^10,11

Immunotherapy in TNBC: A New First-Line Option

NCCN guidelines favor a taxane plus pembrolizumab as first-line therapy for PD-L1–positive, metastatic, triple-negative breast cancer (TNBC) with a disease-free interval over 1 year,^8,12 and recommend pembrolizumab plus neoadjuvant chemotherapy, continued adjuvantly, as standard for high-risk, early-stage TNBC regardless of PD-L1 status, based on a 5-year OS benefit (87% vs 82%) shown in KEYNOTE-522 (NCT03036488).^8,13 For patients with HER2-negative residual disease after neoadjuvant treatment, the CREATE-X trial (UMIN Clinical Trials Registry number, UMIN000000843) demonstrated a benefit with adjuvant capecitabine.¹⁴ NCCN guidelines reserve capecitabine for patients without a germline BRCA mutation,⁸ given the availability of adjuvant olaparib for BRCA-mutated disease, based on the OlympiA trial (NCT02032823).¹⁵ Since the meeting, sacituzumab govitecan (SG) plus pembrolizumab has emerged as a new first-line metastatic option. The ASCENT-04 (NCT05382286) trial showed superior progression-free survival over chemotherapy plus pembrolizumab (11.2 vs 7.8 months),¹⁶ and the combination, along with SG monotherapy, was FDA-approved in frontline PD-L1–positive TNBC in June 2026.¹⁷ Datopotamab deruxtecan (Dato-DXd) was separately approved for first-line TNBC in patients who are not candidates for checkpoint inhibitors or patients who are not candidates for immunotherapy.¹⁸

ADCs: 3 Approved Agents, No Map for Sequencing Them

Trastuzumab deruxtecan is the preferred ADC for HR+/HER2-low and HER2-ultralow metastatic disease, supported by an OS benefit over physician’s-choice chemotherapy (23.9 vs 17.5 months)^19,20; SG is preferred for TNBC based on an OS benefit over chemotherapy in the ASCENT trial (NCT02574455), with the pembrolizumab combination preferred in PD-L1–positive disease based on the ASCENT-04 trial.^16,21 With 3 ADCs now used across overlapping populations, guidance already flagged postprogression sequencing as unresolved, with no head-to-head data or predictive biomarker to guide it. This gap is likely to persist as resistance mechanisms (antigen downregulation, impaired payload internalization) remain incompletely understood. One narrower question has been resolved: SG’s updated label now recommends primary granulocyte colony-stimulating factor prophylaxis starting in cycle 1 for patients at increased risk for neutropenia, replacing what had been an inconsistent practice.¹⁷ Dato-DXd’s expansion since the meeting with additional approvals in HR+/HER2-negative disease and in first-line TNBC²² has exacerbated the sequencing problem—the field now has 3 approved ADCs and still no validated way to choose among them.

HER2+ Early-Stage Disease: Still an Open Question

For node-negative, HER2+ tumors that are 3 cm or smaller, adjuvant paclitaxel plus trastuzumab (the APT regimen [adjuvant paclitaxel and trastuzumab]) remains standard, supported by a 10-year invasive disease-free survival (DFS) rate of 91%.²³ One year of trastuzumab emtansine (the ATEMPT regimen; NCT01853748) is recommended as an alternative for select stage I patients who cannot tolerate weekly visits or have contraindications to paclitaxel, with outcomes comparable across DFS, OS, and breast cancer–specific survival.²⁴ Testing for novel biomarkers such as HER2DX is not currently advised to guide treatment, and is not yet incorporated into NCCN guideline recommendations for early-stage disease.⁸ For patients with HER2+ oligo metastatic disease at diagnosis, a curative-intent approach involving multidisciplinary evaluation, aggressive local therapy, and indefinite HER2-directed maintenance may be appropriate in carefully selected, typically younger and healthier patients with a strong initial response to dual HER2 blockade, though no validated biomarker exists to guide selection.^25,26 Unlike the sections above, this one has not moved: Selection for de-escalation and for curative-intent management in oligometastatic disease still relies on clinical judgment rather than on validated tools.

Three of these 4 areas have shown substantial advancement since November 2024: a new SERD, a new frontline immunotherapy combination, and a third approved ADC. Not all open questions in breast cancer are answered on a predictable timeline, and the standard of care in this disease continues to shift.

References

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