Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Balloon angioplasty of the femoro-popliteal segment: follow up results from southern India.

BACKGROUND: Disease of the femoral and popliteal arteries, though one of the commonest manifestations of atherosclerosis, is under-recognized because the morbidity it produces is less catastrophic than coronary or cerebrovascular arterial involvement. Percutaneous transluminal angioplasty is performed for femoro-popliteal lesions at different centres in India, but post-angioplasty follow up data are scarce. We present our results after femoro-popliteal balloon angioplasty in 140 lesions. METHODS: Between 1986 and 1993, 140 femoro-popliteal angioplasties were performed in 119 patients with symptomatic limb ischaemia. Seventy-one per cent of patients had claudication and the others also had tissue loss. Eighty-two per cent of the lesions were occlusions. The average length of the lesions was 10.7 cm. Conventional wire-balloon angioplasty was performed in 128 lesions; in 12 others, laser-assisted balloon angioplasty was performed using an Nd-YAG laser thermal probe. Patients were followed up at regular intervals for any recurrence of symptoms and for objective evidence of restenosis or re-occlusion. RESULTS: Despite a technical success in 83% of the lesions, cumulative primary patency calculated by the life-table method showed a slow decline which plateaued at 40% after 36 months. Long occlusions and multifocal stenoses showed shorter cumulative patency following angioplasty (27 months and 5.8 months respectively). Extensive luminal irregularity due to post-angioplasty intimal flaps was reduced by using warm contrast for balloon dilatation in 16 patients. In 14 patients who had repeat angioplasty for restenosis, the secondary patency showed a satisfactory figure of 84% at 60 months. CONCLUSION: Percutaneous transluminal angioplasty is a satisfactory alternative to surgery in femoro-popliteal stenotic or occlusive disease. Regular follow up of such patients is essential in the first three years because re-occlusion can occur. We found that patency remained fairly constant after 36 months. Repeated angioplasty can maintain patency in patients with restenosis.

Focal occlusive disease of the common femoral artery: a report of 20 cases.

Occlusive disease localized to the common femoral artery without contiguous involvement of the external iliac and superficial femoral arteries is distinctly uncommon in vascular surgical practice. Twenty patients with focal occlusive disease in 21 common femoral arteries are featured in this report. All except one had severe disabling symptoms: Fontaine classification was stage I in one patient, stage IIb in 13, and stage III in six patients. The probable aetiology, based on clinical features and angiographic observations, was identified as atherosclerosis (nine cases), thromboangiitis obliterans (three) and Takayasu's arteritis (two). Histological features of mucoid vasculopathy, a novel disorder, was seen in one patient while no specific aetiology was evident in five patients. Associated lesions were seen in fourteen patients: aortoiliac in one, femoropopliteal in seven (without any continuity to the common femoral lesion), internal iliac in three and tibial in three. Balloon angioplasty of the common femoral artery lesions was attempted in 14 patients with successful outcome in nine. Three patients (including two with failed balloon angioplasty), underwent thromboendarterectomy and two bypass procedures (iliofemoral, one; femoropopliteal, one). Late reocclusion occurred in one patient each in the angioplasty and surgical groups. There were no procedure-related complications in either group.

Role of angiographic catheters in surgery of popliteal arteriovenous fistulas.

A 50-year-old woman with a chronic, traumatic popliteal arteriovenous fistula was treated surgically by closure of the fistula. Placement of an angiographic catheter across the fistula into the venous sac immediately before surgery helped to locate the fistula accurately and quickly at operation. This simple manoeuvre will facilitate surgical treatment, particularly in cases of long-standing, chronic arteriovenous fistulas.