Background Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. Methods This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n=8; cohort 1), asymptomatic untreated BMs (n=4; cohort 2), or progressing BMs after local therapy (n=9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial overall response rate (ORR-IC) for cohorts 2 and 3. Results As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3–99.7; P<.001). ORR-IC was 50.0% (95%CI, 6.7–93.2) in cohort 2 and 44.4% (95%CI, 13.7–78.8; P<.001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2–74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0–86.7), 80.0% (95%CI, 28.4–99.5) in cohort 1, 50.0% (95%CI, 6.7–93.2) in cohort 2, and 66.7% (95%CI, 29.9–92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade≥3), nausea (42.9%; 0% grade≥3), neutropenia (28.6%; 19% grade≥3), and constipation (28.6%; 0% grade≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. Conclusions T-DXd showed intracranial activity with manageable toxicity and maintained quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.

Breast cancer (BC) is the most common malignancy and the second cause of cancer-specific death in women from high-income countries. Recently, gut microbiota dysbiosis emerged as a key player that may directly and/or indirectly influence development, treatment, and prognosis of BC through diverse biological processes: host cell proliferation and death, immune system function, chronic inflammation, oncogenic signalling, hormonal and detoxification pathways. Gut colonisation occurs during the prenatal period and is later diversified over distinct phases throughout life. In newly diagnosed postmenopausal BC patients, an altered faecal microbiota composition has been observed compared with healthy controls. Particularly, β-glucuronidase bacteria seem to modulate the enterohepatic circulation of oestrogens and their resorption, increasing the risk of hormone-dependent BC. Moreover, active phytoestrogens, short-chain fatty acids, lithocholic acid, and cadaverine have been identified as bacterial metabolites influencing the risk and prognosis of BC. As in gut, links are also being made with local microbiota of tumoural and healthy breast tissues. In breast microbiota, different microbial signatures have been reported, with distinct patterns per stage and biological subtype. Total bacterial DNA load was lower in tumour tissue and advanced-stage BC when compared with healthy tissue and early stage BC, respectively. Hypothetically, these findings reflect local dysbiosis, potentially creating an environment that favours breast tumour carcinogenesis (oncogenic trigger), or the natural selection of microorganisms adapted to a specific microenvironment. In this review, we discuss the origin, composition, and dynamic evolution of human microbiota, the links between gut/breast microbiota and BC, and explore the potential implications of metabolomics and pharmacomicrobiomics that might impact BC development and treatment choices toward a more personalised medicine. Finally, we put in perspective the potential limitations and biases regarding the current microbiota research and provide new horizons for stronger accurate translational and clinical studies that are needed to better elucidate the complex network of interactions between host, microorganisms, and drugs in the field of BC.

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Background: Approximately 30% to 40% of patients (pts) with HER2[+] advanced breast cancer (ABC) will develop brain metastases (BM) during the course of their disease. Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate containing an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In the phase 2 DESTINY-Breast01 trial, T-DXd showed efficacy in the subgroup of HER2[+] ABC pts with stable BM at baseline. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2[+] and HER2-low-expressing ABC pts with a history of BM and/or leptomeningeal carcinomatosis (LMC). Here, we report primary results from cohorts A and C. Methods: This is an ongoing, multicenter, open-label, 5-cohort, non-comparative, phase 2 study across 18 hospitals in 2 countries. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low-expressing ABC with stable, progressing, or untreated BM and/or LMC are being enrolled in 5 cohorts: (A) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (B) HER2[+] or HER2-low-expressing ABC with asymptomatic untreated BM; (C) HER2[+] ABC with progressing BM after local treatment; (D) HER2-low-expressing ABC with progressing BM after local treatment; (E) HER2[+] or HER2-low-expressing ABC with LMC. In cohorts A and C, pts must have received prior taxane and ≥1 HER2-targeted therapy for ABC. Pts received 5.4 mg/kg T-DXd intravenously on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint for cohort A is 16-week progression-free survival (PFS) per local assessment using RANO-BM for central nervous system (CNS) lesions and RECIST v.1.1 for extracranial lesions (H0: 5%); for cohort C, CNS overall response rate (ORR; H0: 10%). A single-arm binomial design is used for cohorts A and C. A futility interim analysis has been planned in cohort A after accrual of 4 pts. Sample size was planned to attain an 80% power at nominal level of one-sided α of 0.05 in each cohort. Results: Between Jun 29, 2020, and Feb 18, 2021, 26 pts were allocated in the study. Enrollment is complete in cohorts A (n=8 pts) and C (n=9 pts), and ongoing in the remaining cohorts. At data cutoff (May 21, 2021), median follow-up for the cohort A was 5.5 months (IQR 4.4-6.9) and 6.2 months (IQR 5.1-6.4) for the cohort C. In the cohort A, 6 (75.0%) of 8 pts were alive without disease progression at 16 weeks, reaching the primary endpoint (p<0.01). In the cohort C, the CNS ORR was 55.6% (5 pts with partial response), also meeting the primary endpoint (p<0.01). At the time of this analysis, 75.0% of pts of the cohort A and 55.6% of the cohort C remained on therapy. The most frequent adverse events of any grade in 26 pts who received at least 1 dose of T-DXd were fatigue (11 [42.3%]; 3.8% of grade 3), nausea (10 [38.5%]), a decreased neutrophil count (9 [34.6%]; 11.5% of grade 3), and anemia (6 [23.1%]). Treatment-related serious adverse events occurred in 1 (3.8%) of 26 pts due to grade 1 pneumonitis. No treatment-related deaths were reported. Conclusions: T-DXd demonstrated preliminary efficacy with manageable toxicity in pretreated pts with HER2[+] ABC with stable and progressing BM after local treatment. Further investigation is required in larger cohorts to validate these findings. The assessment of the T-DXd antitumor activity in cohorts B, D, and E is currently ongoing. Citation Format: Marta Vaz Batista, Patricia Cortez, Manuel Ruiz, Juan Miguel Cejalvo, Juan de la Haba, Laia Garrigós, Fabricio Racca, Sonia Servitja, Salvador Blanch, Iris Teruel, José Manuel Pérez-García, María Gion, Monica Nave, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Sofia Braga. Trastuzumab deruxtecan in patients with HER2[+] or HER2-low-expressing advanced breast cancer and central nervous system involvement: Preliminary results from the DEBBRAH phase 2 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-06.