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The WSG-KEYRICHED-1 phase II trial evaluated a chemotherapy-free neoadjuvant regimen of pembrolizumab plus trastuzumab and pertuzumab in HER2-enriched early breast cancer, achieving a pathological complete response (pCR) rate of 46.5% (95% CI 31.2–62.6%). No survival data (e.g., EFS or OS) were reported, but the regimen showed an acceptable safety profile with no new cardiac toxicity signals. The chemo-free approach suggests promising potential for de-escalation in this subtype, but we’ll need randomized trials to confirm its efficacy and safety.

The INAVO120 trial assessed inavolisib + palbociclib–fulvestrant vs placebo plus palbociclib–fulvestrant in PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer, showing significant improvements in progression-free survival (PFS) (15.0 vs 7.3 months) and overall survival (OS) (34.0 vs 27.0 months). The triplet regimen achieved a higher overall response rate (ORR) (62.7% vs 28.0%), establishing it as a potential new standard for this endocrine-resistant population. Notably, side effects like hyperglycemia, stomatitis, diarrhea, and ocular effects were more frequent with inavolisib.

In summary: It did not work in those patients with stages II-III.

Metronomic dose: low dose cytotoxic therapy at high frequency was studied in combination with an AI (cape at 500mg TID) and showed superiority over AI single agent, this may be an option for patients not tolerating CKD4/6 inhibitors.

Yet another combination to consider after CDK4/6i + ET in HR+ MBC!

Imlunestrant (novel oral SERD) was active in patients with an ESR1 mutations, but otherwise did not offer a benefit in this population of women with ER+ HER2-neg MBC. Overall survival (OS) data is pending with further follow up.

The INSEMA trial showed that for early stage, T1-T2 clinically node negative breast cancer, sentinel lymph node biopsies should not be mandatory, and best clinical judgement can be used.

Another trial with neoadjuvant immunotherapy showing improved results over chemotherapy alone. (12% higher PCR 48% vs 36%).

Dato-DXd is now approved in HR+, HER2-neg, metastatic breast cancer after prior therapy with endocrine-based therapy and chemotherapy. There was an impressive reduction in the risk of death or progression with an HR of 0.63. Watch out for ocular and pulmonary toxicity. HER2-ultra low testing will be burdensome but must be done for drug approval.

TD beat chemotherapy after failure of hormonal therapy in HER-2 low and ultra low. Wait for the indication.