Aberrations in the PI3K signaling pathway are frequently observed in patients with breast cancer. Because of that, PI3K inhibitors are attractive options for the treatment of breast cancer because PI3K is the most proximal component of the pathway other than receptor tyrosine kinases. Buparlisib is a potent and highly specific oral pan-class I PI3K inhibitor, which is currently under investigation in patients with breast cancer. In this article, we describe the PI3K signaling pathway, the prognostic value of PI3K pathway mutations, as well as the mechanism of action of buparlisib. Lastly, we discuss preliminary results of preclinical and clinical studies showing the efficacy and safety profile of this agent in breast cancer patients.
Background: HER2 amplification is frequent in DCIS and is associated with poor prognosis features. This study aimed to determine the molecular effects in Ras/Raf/MAK and PI3K/AKT signaling pathway of the HER2 inhibitor lapatinib in patients with HER2 positive DCIS as well as correlation with radiological and pathological response. Patients and Methods: Patients (pts) with HER2 positive DCIS received 1500 mg daily of lapatinib for 4 consecutive weeks prior to surgical resection. Changes in tumor volume were evaluated by MRI. The molecular effects of lapatinib on apoptotic level (TUNEL), cell proliferation (Ki67) and HER2 signaling pathway were determined in pre and post-treatment tumor biopsies. Results: A total of 20 pts were included. Lapatinib was well tolerated with only minor and transient side effects reported. The agent effectively modulated HER2 signaling by affecting cell cycle kinetics through decreasing cytoplasm pERK1 in 11 pts with no change or slight increase activation in 5 pts. Of those 11 pts: eight had parallel inactivation of pHER2, two pts had paradoxical activation of pAkt and three pts had an increase in apoptotic level. In addition, seven pts also presented with decrease in MRI signal intensity and tumor size. Conclusions: Four weeks of lapatinib for patients with HER2-positive DCIS result in significant antiproliferative changes through RAS/MAPK signaling pathway together with a decrease in MRI signal. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-15.
Background: DCIS is a heterogeneous disease, with increasing incidence. Up to 37% of DCIS overexpress HER2. Lapatinib is a tyrosine kinase inhibitor that directly inhibits HER2 receptor signaling by blocking the receptor's kinase activity. This work tested the hypothesis that Lapatinib inhibits Ras/Raf/MAK and PI3K/AKT signaling in HER2 positive DCIS. Patients and Methods: Patients with HER2 positive (FISH rate >2.2) DCIS diagnosed by core needle biopsy with low risk of having a hidden invasive component were eligible. Neoadjuvant Lapatinib 1500mg daily was administered for 4 weeks prior to surgical resection. EGFR was analyzed by FISH in the biopsy specimen. Ki67, PTEN, AKT, pAKT and pERK were evaluated by IHQ. PI3KCA mutations were screened at exons 9 and 20 by PCR. Apoptosis was analyzed by TUNEL assay. All biological markers were measured before and after Lapatinib treatment. Results: Eleven pts with HER2 positive DCIS have been included to date. Median FISH amplification was 7 (range 2, 70-14). Evaluation pre-Lapatinib showed that: none of the pts had EGFR amplification; six pts (54%) had a Ki67 >25%; pAKT was overexpressed in 3 pts (27%) and pERK in 2 pts (18%); PTEN was deleted in 3 pts (27%). PI3KCA mutations were detected in only 1 pt (9%). After Lapatinib treatment, 9 pts were evaluable. We observed a trend for inactivation of the Ras/Raf/MAK signaling pathway in 7 pts (70%) patients. Interestingly, 3 of these pts had paradoxical activation of PI3K/Akt suggesting a compensatory feed back loop. One out of these 3 pts has PTEN deleted. In addition, 3 pts (33%) showed an increase in the apoptotic index. Conclusions: In our study, four weeks of Lapatinib against HER2 positive DCIS resulted in inactivation of Ras/Raf/MAK pathway; however an activation of the PI3K/Akt was seen as the same time in 3 pts. Nevertheless this trend needs to be confirmed with the inclusion of more pts. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-17.
Background: The PI3K/AKT/mTOR signaling pathway plays a key role for the growth and survival of breast cancer cells and aberrations such as phosphatidylinositol-3-kinase (PI3KCA) mutations are common. BKM120 is an oral pan-class I PI3KCA inhibitor. The aim of this study was to evaluate neoadjuvant treatment with BKM120 in PI3KCA mutated early breast cancer in order to assess the effect in PI3K/Akt/mTOR signalling pathway. Methods: Patients (pts) with previously untreated invasive, non-metastatic histologically confirmed breast cancer, with a tumor size ≥ 1,5cm and non-urgent surgical treatment were enrolled. Only women with ER+ / HER2- and PI3KCA gene mutated were eligible. Patients received treatment with BKM120 (100mg/day; administered orally) during 4 weeks. Subsequently, surgery was performed. Inmunohistochemical analysis of pAkt and pS6 (the H-score intensity x%) as well as KRAS mutation were evaluated on tumor tissue at surgery. H score < 150 was related with inactivation of PI3K signalling pathway. Results: To date 24 patients has been included in the study (median age, 52,5 years; range 38-69 years;). 13 out of 24 (54%) had PI3KCA mutated and 8 have completed BKM120 treatment. PI3KCA mutation: Exon 20, 4 pts; exon 9, 2 pts; exon 4, 1 pts and exon 20 and 9, 1 pts. One patient discontinued treatment due to adverse event (nausea grade 2). The most relevant adverse events included transitory increase of transaminases. No serious or grade 4 adverse events were observed. Preliminary results of 7 pts showed inactivation of pAkt (H score < 150) in 2 pts with no change in the reminder 5 pts (median H score 300). Conclusion: Our preliminary data shown that four weeks of BKM120 treatment do not inactivate PI3K/Akt/mTOR signalling pathway, measured throughout pAkt in ER+/HER2-/PI3KCA mutated breast cancer pts. However, we cannot draw any conclusion because the small number of pts included so far. KRAS mutation and pS6 analysis will be presented along with updated results. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-09.
Purpose: The Her2/neu gene is amplified and/or its protein is overexpressed in 15-25% of invasive breast cancer, but in Ductal Carcinoma In Situ (DCIS) this expression is highly increased (60-80%). We review our rate of DCIS with Her2 amplified in a prospective series of women with new diagnosis of DCIS. Methods: Patients with new diagnosis of DCIS by biopsy were studied. The status of Her2 was evaluated by fluorescence in situ hybridization (Vysis path vision HER-2 DNA probe kit) and was considered amplified if the ratio HER2/CEP17 was >2.0. The status of estrogen and progesterone receptors were analyzed by inmunohistochemistry (IHQ). Data evaluating architectural pattern and histological grade were also collected. Results: Data from 53 patients with DCIS were included (two patients with combined invasive ductal carcinoma detected at time of surgery and 51 cases of pure DCIS). HER2 was amplified in 20 patients (37%), with HER2/CEP17 ratios between 2.16 to 14.00. A total of 29 patients had grade III DCIS, and of those 18 (62%) had Her2 amplified. 17 patients (32%) were estrogen and progesterone receptors negative (10 with Her2 amplified). We have not observed any correlation about architectural pattern (comedo, cribriform, micropapillary, solid/necrotic) and amplification of Her2. Conclusion: In our series of DCIS patients the Her2 amplification was less commonly found compared to prior studies (37% vs >60%). Most of DCIS were grade 3 (90%) and no relation was found among the architectural pattern and amplification of Her2. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-06.
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