No abstract

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

The current model for breast cancer progression proposes independent ‘low grade (LG)‐like’ and ‘high grade (HG)‐like’ pathways but lacks a known precursor to HG cancer. We applied low‐coverage whole‐genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG‐like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent ‘low grade‐like’ and ‘high grade‐like’ pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mullerian adenosarcoma is a neoplasm composed of benign mullerian epithelium and a sarcomatous stroma. This tumor classically occurs in the endometrium of postmenopausal women and less frequently in the extrauterine genital tract. Rare cases of extragenital adenosarcoma have been reported. We present the case of a 23-year-old female who presented with an extragenital adenosarcoma arising in an endometriotic cyst in the pouch of Douglas. The patient was treated with local excision, chemotherapy and radiotherapy. At 2 years follow-up she was disease-free. The literature on extragenital adenosarcoma is reviewed. These tumors are clinically more aggressive than their uterine counterparts. Surgical excision is the initial treatment modality for these patients. Little information is available regarding the efficacy of adjuvant chemotherapy or radiotherapy. This is an area that requires further study.

A 38-year-old woman developed an acute, painful cutaneous eruption on her lower legs, neck, chest and fingers while receiving a number of oral and intravenous antibiotics for left leg cellulitis caused by trauma. Clinically and histopathologically, she was diagnosed with Sweet's syndrome with typical pseudovesicular skin changes in conjunction with erythema nodosum-like lesions on her lower legs. She responded quickly to oral prednisolone. We propose Staphylococcal cellulitis as a cause of Sweet's syndrome.