PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 509-509 ◽  
Author(s):  
Mafalda Oliveira ◽  
Alejandro Navarro ◽  
Leticia De Mattos-Arruda ◽  
Gessamí Sánchez-Ollé ◽  
Meritxell Bellet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Pik3ca Mutation ◽  
Metastatic Breast ◽  
Mtor Inhibitors ◽  
Pi3k Pathway ◽  
Time To Progression ◽  
Prospective Trials

509 Background: The role of PI3Kp dysregulation as a predictor of sensitivity to PI3Kpi is unclear. We aimed to evaluate the efficacy of PI3Kpi in two cohorts of MBC pts with assessable PI3Kp status. Methods: MBC pts treated in ≥3rd line with PI3Kpi were reviewed. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore≤50). Cohort A: pts treated with single agent PI3Kpi. Cohort B: pts treated with PI3Kpi in combination with hormonal therapy (HT), chemotherapy (CT) and/or trastuzumab (T). Results: Out of 232 MBC pts screened for PI3Kp alterations from Sep09 to Sep11, 32 were treated with PI3Kpi. Cohort A (n=17): HR+/HER2- 88%, HER2+ 6%, triple negative 6%; median age 43, median MBC lines 4 (2-9); PIK3CAmut in 10/17 (58.8%; 6 exon9, 4 exon20), PTEN low 3/17 (17.6%), 1 pt both; PI3Kp dysregulation 12/17 pts. Cohort B (n=15): HR+/HER2- 40%, HER2+ 60%; median age 49, median MBC lines 4 (2-13); PIK3CAmut 3/13 assessable (23.1%; all exon20), PTEN low 6/15 (40%), 1 pt both; PI3Kp dysregulation 8/15 pts. Time to progression to PI3Kpi (TTP), overall survival from MBC diagnosis (OSMBC) and OS from PI3Kpi beginning (OSPI3Kpi), according to PIK3CA status and PI3Kp dysregulation, are shown. No differences were found according to PTEN status. Conclusions: These results suggest that the best outcomes with PI3Kpi in PIK3CAmut MBC pts occur when they are used in combination with HT/CT/T. Activity of non selective PI3Kpi used as single agents seems to be limited, making results from prospective trials with selective PI3Kα inhibitors and PI3Kpi in combinations eagerly awaited. [Table: see text]

Triple Negative Breast Cancer Pathologic Diagnosis and Current Chemotherapy Treatment Options

2014 ◽  
Vol 10 (01) ◽  
pp. 25
Author(s):  
Bernardo L Rapoport ◽  
Simon Nayler ◽  
Georgia S Demetriou ◽  
Shun D Moodley ◽  
Carol A Benn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Treatment Options ◽  
Single Agent ◽  
Pathologic Complete Response ◽  
Metastatic Breast ◽  
Pathologic Diagnosis ◽  
Metastatic Setting

Triple negative breast cancer (TNBC) comprises 12–20 % of all breast cancers and are a heterogeneous group of tumors, both clinically and pathologically. These cancers are characterized by the lack of expression of the hormone receptors estrogen receptor (ER) and progesterone receptor (PR), combined with the lack of either overexpression or amplification of the human epidermal growth factor receptor-2(HER2)gene. Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay of treatment of this disease in the neoadjuvant, adjuvant, and metastatic setting. The lack of predictive markers in identifying potential targets for the treatment of TNBC has left a gap in directed therapy in these patients. Platinum agents have seen renewed interest in TNBC based on an increasing body of preclinical and clinical data suggesting encouraging activity. However, comparisons between chemotherapy regimens are mostly retrospective in nature and the best agents or drug combinations for TNBC have not been established in prospective randomized trials. Numerous studies have now shown that TNBC has significantly higher pathologic complete response (pCR) rates compared with hormone receptor positive breast cancer when treated with neoadjuvant chemotherapy, and pCR correlates well with better outcomes for these patients. Patients with TNBC account for a larger number of deaths in the setting of metastatic breast cancer. There is no preferred treatment for the first-line metastatic setting. Although individual agents are recommended, given the often aggressive nature of TNBC and the presence of extensive visceral disease, the use of a combination of drugs, rather than a single agent, is often advocated. This review article will outline the pathologic diagnosis of TNBC and the treatment options available to these patients in the neoadjuvant, adjuvant, and metastatic setting, including an assessment of future directions of treatment.

Phase II study of apatinib plus vinorelbine, a novel combination of all-oral regimen in heavily pretreated patients with metastatic HER2-negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS1123-TPS1123
Author(s):  
Anjie Zhu ◽  
Peng Yuan ◽  
Jiayu Wang ◽  
Fei Ma ◽  
Yang Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Triple Negative ◽  
Phase Ii Study ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Oral Vinorelbine ◽  
Heavily Pretreated

TPS1123 Background: Antiangiogenic therapy in combination with chemotherapy is effective in control advanced breast cancer(ABC). Apatinib is an oral, highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). Phase II clinical trials of Apatinib single agent had presented objective response and manageable toxicity in heavily pretreated, metastatic breast cancer. The median progression free survival (PFS) and median overall survival (OS) of single agent in both triple-negative and non-triple-negative breast cancer were 3.3-4.0 months and 10.3-10.6 months, respectively. The overall response rate and disease control rate (DCR) reached 16.7% and 66.7%, respectively. This all-oral phase II study aims to investigate the efficacy and safety of the oral vinorelbine-Apatinib combination in pre-treated metastatic breast cancer(MBC). Methods: This single arm prospective study enrolled patients with HER2(Human epidermal growth factor receptor-2 ) negative advanced breast cancer, pretreated with anthracycline and taxanes, and who failed in the metastatic setting at least one prior chemotherapy regimen. The estimated Enrollment was 40 patients.The primary end point of this study was PFS. Secondary end points included objective response rate (ORR), DCR, OS and safety. Patients were treated with apatinib 500/425mg daily plus oral vinorelbine 60-80 mg/m2 day1,8,15 every 3 weeks/cycle. Starting doses of Apatinib were chosen according to age, weight and patient status. Patients eligible were evaluated by CT or MRI scan at baseline and every 2 cycles (6 weeks) there after until disease progressed. Adverse events (AEs) were assessed and graded in accordance with the Common Terminology Criteria for AEs, version 4.0. Clinical trial information: NCT02768415.

scholarly journals Breast Cancer Immunotherapy: From Biology to Current Clinical Applications

2020 ◽  
pp. 113-124
Author(s):  
Jorge Henrique Santos Leal ◽  
Heather McArthur
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Immune Checkpoint ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Metastatic Breast ◽  
Response Rates ◽  
Phase Iii

Therapeutic strategies for the treatment of breast cancer have historically been determined by the presence or absence of hormone receptors and HER2 amplification and/or protein expression. For patients with breast cancer that lack these biomarkers, the so-called ‘triple-negative’ subtype, chemotherapy has been the cornerstone of cure and palliation. However, with the recent successful development of immune checkpoint molecules that target cytotoxic T-lymphocyte antigen-4, programmed cell death-1 (PD-1), and PD-ligand 1 (PD-L1), improved survival has been reported across a range of tumour types including melanoma, lung, and bladder cancer. In metastatic breast cancer, trials of single-agent immune checkpoint inhibitors (ICI) have resulted in limited overall response rates; however, strategies that combine local or systemic therapies with ICI have improved response rates and, in some cases, improved survival. For example, the addition of an anti-PD-L1 inhibitor, atezolizumab, to nab-paclitaxel chemotherapy for newly diagnosed metastatic triple-negative breast cancer demonstrated an improvement in overall survival in an informal analysis of the PD-L1-positive subset in a recently reported Phase III clinical trial. These results ultimately led to U.S. Food and Drug Administration (FDA) approval for an ICI for the treatment of breast cancer, with numerous other health authorities following suit. Herein, the authors describe the biology behind ICI, the rationale for ICI administration in breast cancer, the related clinical trial data reported to date, and promising future strategies.

Phase II, two-stage, two-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer (EC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5524-5524 ◽  
Author(s):  
Andrea P. Myers ◽  
Russell Broaddus ◽  
Vicky Makker ◽  
Panagiotis A. Konstantinopoulos ◽  
Ronny Drapkin ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Single Agent ◽  
Objective Response ◽  
Pik3ca Mutation ◽  
Mtor Inhibitors ◽  
Skin Toxicity ◽  
Pi3k Pathway ◽  
Pik3ca Mutations ◽  
Primary Endpoints ◽  
Grade 3

5524 Background: EC has high rates of PI3K pathway alteration including PTEN mutation (50%) or IHC loss (>50%), PIK3CA mutation (25-40%) and PIK3R1 (20%) mutation. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized that pts whose tumors harbored PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. Methods: Pts had recurrent or advanced EC; all histologies except MMMT were eligible. Up to 2 prior chemo lines were permitted; excluding prior treatment with PI3K/MTOR inhibitors. The first 19 pts were treated with MK-2206 200mg QW; due to initial skin toxicity rates, the starting dose was amended to 135mg QW. Co-primary endpoints were objective response and 6 mo PFS. The first 37 pts were stratified retrospectively. PIK3CA MT included R88Q, K111N, E110K, E418K, C420R, E453K, E542K/V,E545K, Q546R, H701P, M1043V, H1047R/L/Y changes. Independent Simon 2-stage tests were planned within PIK3CA MT and WT stratum: for MT, n1=15 and n2=10 pts would allow discrimination of RR<5% and 6moPFS<10% versus RR>25% or 6moPFS>35%; for WT, n1=31 and n2=24 pts would discriminate RR<5% and 6moPFS<10% versus RR>20% or 6moPFS>25%. Results: 37 pts were enrolled (1 ineligible) before accrual was stopped as timely CLIA-compliant prospective mutation analysis was not feasible. By PIK3CA mutation analysis, 9 pts were MT: 1 pt had both PR and 6moPFS. 27 pts were WT: 1 pt had PR and 3 pts had 6moPFS. 2 pts with 6moPFS were treated at 200mg; 2 pts with 6moPFS were treated at 135mg. Each group had 1 PR. The most common toxicity was grade 3 rash (19%). Grade 3 and 4 toxicities occurred in 50% and 8% of pts. Exploratory analysis of histology found all pts with 6moPFS were classified as serous (4 of 8) as compared to all other histologies (0 of 28, p=.001). Targeted exome sequencing and copy number analysis of the PI3K pathway and PTEN IHC are underway. Associative studies will be reported. Conclusions: There is limited single agent activity of MK-2206 in both PIK3CA MT and PIK3CA WT EC populations. Activity was detected in pts with serous histology tumors and warrants further study. Clinical trial information: NCT01307631. [Table: see text]

Use of alpelisib in the treatment of hormone receptor positive metastatic breast cancer: An institutional experience.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15216-e15216
Author(s):  
Tsering G. Lama Tamang ◽  
Daniel Kyung ◽  
Lauren Eisenbud ◽  
Tianyi Tang ◽  
Ritesh Parajuli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Pik3ca Mutation ◽  
Metastatic Breast ◽  
Pi3k Pathway ◽  
Real World Data ◽  
Tumor Registry ◽  
Hormone Receptor Positive ◽  
Heavily Pretreated ◽  
Institutional Experience

e15216 Background: Mutations in PI3K pathway is a known mechanism of resistance to endocrine therapy in breast cancer. Alpelisib is an alpha-specific PI3K inhibitor. Alpelisib with Fulvestrant is approved for treatment (Tx) of PIK3CA mutated HR+ metastatic breast cancer (MBC) that progress on hormonal therapy. Despite its approval by the FDA, real world data on the use of Alpelisib for the management of MBC is lacking. This abstract reviews the safety and efficacy of Alpelisib in the management of patients with MBC. Methods: A retrospective review of the tumor registry database at a single institution was conducted to identify patients with HR+ MBC. Detailed clinical and pathologic data of PIK3CA mutated patients treated with Alpelisib were obtained. Genomic profiling was done with Foundation One. Results: Table highlights the characteristics of the four patients. All were treated with Alpelisib and Fulvestrant after PIK3CA mutation was demonstrated. 3 patients were heavily pretreated with systemic Tx including CDK 4/6 inhibitors. All patients responded to Alpelisib and Fulvestrant despite treatment history. Mucositis, rash, hyperglycemia and pancytopenia were the observed adverse events (A/E). All A/E were adequately managed except in one patient that required discontinuation of Tx. None has clinically progressed. Conclusions: Our data suggests that Alpelisib and Fulvestrant is tolerated and improves outcomes in patients with HR+ MBC. Alpelisib and Fulvestrant could be an effective therapy in patients who have also progressed on systemic chemotherapy including CDK 4/6 inhibitors. Although our sample size is small, we hope that our experience could guide clinicians in the management of patients with HR+ MBC who harbor the PIK3CA mutation and are being treated with Alpelisib. [Table: see text]

scholarly journals Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2−negative endocrine-refractory metastatic breast cancer

2020 ◽  
Vol 8 (1) ◽  
pp. e000173 ◽  
Author(s):  
Ami N Shah ◽  
Lisa Flaum ◽  
Irene Helenowski ◽  
Cesar A Santa-Maria ◽  
Sarika Jain ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Phase Ii Study ◽  
Single Agent ◽  
Metastatic Breast ◽  
Low Grade ◽  
Hormone Receptor Positive

BackgroundResponse rates to single agent immune checkpoint blockade in unselected pretreated HER2−negative metastatic breast cancer (MBC) are low. However, they may be augmented when combined with chemotherapy.MethodsWe conducted a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) MBC who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2by mouth twice daily on days 1–14 of a 21-day cycle. The primary end point was median progression-free survival (mPFS) compared with historic controls and secondary end points were overall response rate (ORR), safety and tolerability. The study had 80% power to detect a 2-month improvement in mPFS with the addition of pembrolizumab over historic controls treated with capecitabine alone.ResultsThirty patients, 16 TN and 14 HR+ MBC, were enrolled from 2017 to 2018. Patients had a median age of 51 years and received a median of 1 (range 0–6) prior lines of therapy for MBC. Of 29 evaluable patients, the mPFS was 4.0 (95% CI 2.0 to 6.4) months and was not significantly longer than historic controls of 3 months. The median overall survival was 15.4 (95% CI 8.2 to 20.3) months. The ORR was 14% (n=4), stable disease (SD) was 41% (n=12) and clinical benefit rate (CBR=partial response+SD>6 months) was 28% (n=8). The ORR and CBR were not significantly different between disease subtypes (ORR 13% and 14%, CBR 25% and 29% for TN and HR+, respectively). The 1-year PFS rate was 20.7% and three patients have ongoing responses. The most common adverse events were low grade and consistent with those seen in MBC patients receiving capecitabine, including hand-foot syndrome, gastrointestinal symptoms, fatigue and cytopenias. Toxicities at least possibly from pembrolizumab included grade 3 or 4 liver test abnormalities (7%), rash (7%) and diarrhea (3%), as well as grade 5 hepatic failure in a patient with liver metastases.ConclusionsCompared with historical controls, pembrolizumab with capecitabine did not improve PFS in this biomarker unselected, pretreated cohort. However, some patients had prolonged disease control.Trial registration numberNCT03044730.

Phase II Trial of Trastuzumab Followed by Weekly Paclitaxel/Carboplatin As First-Line Treatment for Patients With Metastatic Breast Cancer

2004 ◽  
Vol 22 (9) ◽  
pp. 1621-1629 ◽  
Author(s):  
Howard Burris ◽  
Denise Yardley ◽  
Suzanne Jones ◽  
Gerry Houston ◽  
Catherine Broome ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
Median Time ◽  
Median Overall Survival ◽  
Response Rate ◽  
Single Agent ◽  
Metastatic Breast ◽  
Weekly Paclitaxel ◽  
Time To Progression

Purpose To determine the response rate of trastuzumab as first-line therapy in patients with HER-2 overexpressing metastatic breast cancer. To assess the feasibility and toxicity of weekly paclitaxel/carboplatin with or without trastuzumab following initial treatment with trastuzumab. Patients and Methods Sixty-one patients received trastuzumab (8 mg/kg followed by 4 mg/kg/wk) for 8 weeks. Responding patients received 8 additional weeks of trastuzumab (4 mg/kg/wk), and then proceeded to receive trastuzumab (2 mg/kg) in combination with paclitaxel 70 mg/m2 and carboplatin (area under the curve, 2) weekly for 6 weeks followed by 2 weeks rest. Stable patients after the initial 8 weeks of trastuzumab proceeded to treatment with trastuzumab, paclitaxel, and carboplatin. Patients with disease progression during the initial 8 weeks had the trastuzumab discontinued and were treated with weekly paclitaxel/carboplatin. Results Weekly paclitaxel/carboplatin with or without trastuzumab was well tolerated. Fifty-two patients were assessable for response and all 61 patients were assessable for survival. Seventeen (33%) of 52 patients experienced a minor/partial response to single-agent trastuzumab and received 8 additional weeks of single-agent trastuzumab. Fifteen (29%) of 52 patients had stable disease and proceeded to receive paclitaxel/carboplatin/trastuzumab. Thirty-one patients with measurable disease were assessable for response after initial single-agent trastuzumab followed by paclitaxel/carboplatin/trastuzumab. An overall response rate of 84% (eight complete responses/18 partial responses), median time to progression of 14.2 months, and median overall survival of 32.2 months was reported with the triplet combination. In the patients treated with paclitaxel/carboplatin alone after disease progression on initial single-agent trastuzumab, an overall response rate of 69% (one complete response/10 partial responses), median time to progression of 8.3 months, and median overall survival of 22.2 months was reported. Median time to progression for all 61 patients is 10 months and the median overall survival is 26.7 months. Conclusion This trial confirms the activity and tolerability of weekly paclitaxel/carboplatin alone or in combination with trastuzumab in women with HER-2 overexpressing metastatic breast cancer.

scholarly journals Current problems in the first-line treatment of metastatic breast cancer: focus on the role of docetaxel

2010 ◽  
Vol 4 (3) ◽  
pp. 97-107
Author(s):  
Filippo Montemurro
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Complete Remission ◽  
Liver Metastases ◽  
Single Agent ◽  
Metastatic Breast ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

Metastatic breast cancer is a very heterogeneous disease, both from a clinical and a biological point of view. Despite being still incurable, the expanding therapeutic repertoire has determined a progressive increase in median survival. We describe the clinical course of a 67-year-old woman with a locally advanced, hormone-receptor positive breast cancer with synchronous liver metastases. Single-agent docetaxel at the dose of 100 mg/m2 for 8 cycles determined a pathological complete remission in the breast and a near complete remission of liver metastases. After more than 4 years from diagnosis, the patient is alive and without signs of tumour progression. Based on this clinical case, we discuss management issues like the choice of the initial treatment, the use of monochemotherapy vs polychemotherapy, the worth of surgery of the primary tumour in patients with stage IV disease, and the issue of maintenance endocrine therapy. Furthermore, we reviewed the pivotal role of docetaxel in the management of advanced breast cancer. Whether monochemotherapy or polychemotherapy is felt to be an adequate choice in the clinical practice, docetaxel qualifies as one of the most active and manageable agents. Single agent activity ranging from 20-48% in terms of response rate has been reported in several clinical trials in patients treated in various clinical settings. Docetaxel-based combinations with other cytotoxic agents have become established in the first line treatment both in patients with anthracycline-resistant and anthracycline-sensitive metastatic breast cancer. Finally, docetaxel has been shown to be an optimal companion drug for biologically targeted agents like trastuzumab or bevacizumab, resulting in further treatment options.

Triple Negative Breast Cancer Pathologic Diagnosis and Current Chemotherapy Treatment Options

2014 ◽  
Vol 10 (01) ◽  
pp. 35 ◽  
Author(s):  
Bernardo L Rapoport ◽  
Simon Nayler ◽  
Georgia S Demetriou ◽  
Shun D Moodley ◽  
Carol A Benn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Treatment Options ◽  
Single Agent ◽  
Metastatic Breast ◽  
Complete Response ◽  
Breast Cancers ◽  
Metastatic Setting

Triple negative breast cancer (TNBC) comprises 12–20 % of all breast cancers and are a heterogeneous group of tumours, both clinically and pathologically. These cancers are characterised by the lack of expression of the hormone receptors oestrogen receptor (OR) and progesterone receptor (PR), combined with the lack of either overexpression or amplification of the human epidermal growth factor receptor-2 (HER2) gene. Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay of treatment of this disease in the neoadjuvant, adjuvant and metastatic setting. The lack of predictive markers in identifying potential targets for the treatment of TNBC has left a gap in directed therapy in these patients. Platinum agents have seen renewed interest in TNBC based on an increasing body of preclinical and clinical data suggesting encouraging activity. However, comparisons between chemotherapy regimens are mostly retrospective in nature and the best agents or drug combinations for TNBC have not been established in prospective randomised trials. Numerous studies have now shown that TNBC has significantly higher pathological complete response (pCR) rates compared with hormone receptor positive breast cancer when treated with neoadjuvant chemotherapy, and pCR correlates well with better outcomes for these patients. Patients with TNBC account for a larger number of deaths in the setting of metastatic breast cancer. There is no preferred treatment for the first-line metastatic setting. Although individual agents are recommended, given the often aggressive nature of TNBC and the presence of extensive visceral disease, the use of a combination of drugs, rather than a single agent, is often advocated. This review article will outline the pathological diagnosis of TNBC and the treatment options available to these patients in the neoadjuvant, adjuvant and metastatic setting, including an assessment of future directions of treatment.

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