Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial

Introduction: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I-III BC. Materials and methods: Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. Results: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). Conclusion: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population

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Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial.

INTRODUCTION: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I-III BC. MATERIALS AND METHODS: Two doses of weekly oral MK2206 were administered at days - 9 and - 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. RESULTS: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). CONCLUSION: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.

Staging resection and reconstruction with temporary wound VAC coverage in a case of giant cystosarcoma phyllodes of the breast.

INTRODUCTION: Cystosarcoma phyllodes (CP) is a rare breast tumor occurring most often in females in their fifth decade. While usually benign, some CP tumors exhibit aggressive growth patterns and extensively invade chest wall structures; resecting these tumors to negative surgical margins can be challenging. We present a case of malignant CP involving the chest wall where using a negative pressure vacuum-assisted closure (VAC) system after resection enabled complete histopathologic margin assessment prior to reconstruction. This is the first known report of staged breast tumor resection and reconstruction with interim VAC coverage. CASE PRESENTATION: A 48 year-old woman presented with rapidly increasing left breast size, fevers, and fatigue. On examination, the left breast was massively enlarged with engorged vessels and skin necrosis. Lab analyses revealed unusual metabolic abnormalities requiring preoperative hospitalization. We performed a left modified radical mastectomy with partial resection of pectoralis major and minor muscles, temporarily sealing the wound with a VAC due to concern for deeper tumor extension that could require further resection. Pathology revealed malignant CP with a negative deep margin. The 38cm defect was then repaired with latissimus myocutaneous flap plus skin graft. At three-year follow up the patient remains free of disease. CONCLUSION: In cases of malignant CP involving the chest wall, minimizing the extent of chest wall resection is critical for reducing morbidity, while completely clearing tumor margins is essential for reducing recurrence risk. Using temporary wound VAC coverage enables cautious debulking followed by histopathologic margin assessment prior to definitively reconstructing the breast.

Nipple-sparing mastectomy: indications, oncologic safety.

The locoregional treatment of breast cancer has rapidly evolved from disfiguring approaches to nipple-sparing mastectomy (NSM) in selected patients. The goal of the nipple-sparing mastectomy procedure is to remove all glandular breast tissue in order to maximize oncologic therapy, while leaving the nipple-areola complex (NAC) in place in order to optimize aesthetics of the breast. The procedure is gaining popularity around the world, both for treatment of known breast cancer and for prophylaxis in high risk patients. This article reviews indications and patient selection criteria, surgical techniques, as well as oncologic outcomes of the NSM procedure. NSM requires multidisciplinary collaboration amongst breast cancer specialties both preoperatively and postoperatively. The patient should be counseled regarding possibility of NAC removal in the event of retroareolar malignancy identified on frozen section pathology. The patient should also be counseled regarding potential loss of sensation and ischemia in the postoperative period that may require NAC excision. Patient satisfaction remains after NSM high, particularly when compared to the skin-sparing (without sparing of the NAC) mastectomy. The American Society of Breast Surgeons has established a NSM Registry, in order to prospectively collect data on metrics utilized, surgical techniques, and oncologic as well as aesthetic outcomes so that evidence based outcome measures for this procedure can be evaluated.