Demonstrating the feasibility of collecting secondary, de-identified data on Australian patients receiving treatment as part of a Medicine Access Programme.

BACKGROUND: In Australia, data generated from the carefully selected, treated and monitored patients enrolled in clinical trials largely inform routine care and funding approvals. Medicine Access Programmes (MAP) enable drug access and while potentially a rich source of data, historically have not collected data beyond a participant list. AIMS: To explore the feasibility of using MAP to identify patient populations for inclusion in non-interventional studies. METHODS: Clinicians affiliated with the Walter and Eliza Hall Institute engaged with Roche to implement PeRSIA, a secondary data use non-interventional study of patients receiving neoadjuvant pertuzumab for non-metastatic HER2+ breast cancer. The study utilised a pre-existing Roche-sponsored MAP to identify clinicians as data contributors. Data security, ownership and reporting issues were addressed utilising the BioGrid platform and standards developed for existing Walter and Eliza Hall Institute registries. Disease experts developed project-specific Case Report Forms documenting treatment, surgical and cancer-specific outcomes, and adverse events. RESULTS: To date, 12 of 16 (75%) clinicians approached to participate in PeRSIA are contributing de-identified data. From February through September 2018, data on 41 patients from seven centres were collected. Median patient age is 56 years (range 36-81), 36 (88%) had Stage 2 to 3 disease and 27 (66%) were node positive. The median number of cycles of neoadjuvant pertuzumab planned was 4. CONCLUSIONS: This initial report is, to our knowledge, the first description of a secondary data use non-interventional study collecting comprehensive data on patients enrolled, independently, in a MAP. This effort continues and opportunities with other industry partners are being pursued.

A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2-Positive Metastatic Breast Cancer.

Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0-8) were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). Apart from uncomplicated "on-target" lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations. SIGNIFICANCE: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors.See related commentary by Drago et al., p. 323.This article is highlighted in the In This Issue feature, p. 305.

RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers.

Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.