Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial

Schmid, Peter; Abraham, Jacinta; Chan, Stephen; Wheatley, Duncan; Brunt, Adrian Murray; Nemsadze, Gia; Baird, Richard D.; Park, Yeon Hee; Hall, Peter; Perren, Timothy; Stein, Robert; Mangel, László; Ferrero, Jean-­Marc; Phillips, Melissa; Conibear, John; Cortés, Javier; Foxley, Andrew; Bruin, Elza C. de; McEwen, Robert; Stetson, Daniel; Dougherty, Brian; Sarker, Shah-Jalal; Prendergast, Aaron; McLaughlin-Callan, Max; Burgess, Matthew; Lawrence, Cheryl; Cartwright, Hayley; Mousa, Kelly; Turner, Nicholas C.

doi:10.1200/jco.19.00368

Cited by 264 publications

(190 citation statements)

References 26 publications

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“…As discussed above, LAR subtype shares similar features with luminal HR-positive disease. Consistent with luminal type behavior is the fact that in subset analyses of neoadjuvant studies LAR showed the lowest pCR rate compared to other TN-phenotypes [104,105]. Interestingly, despite the low pCR rate LAR subtype seems to be associated with better survival outcomes [106].…”

Section: Targeting Ar Pathwaymentioning

confidence: 76%

The Landscape of Targeted Therapies in TNBC

Vagia

Mahalingam

Cristofanilli

2020

Cancers

255

198

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Triple negative breast cancer (TNBC) constitutes the most aggressive molecular subtype among breast tumors. Despite progress on the underlying tumor biology, clinical outcomes for TNBC unfortunately remain poor. The median overall survival for patients with metastatic TNBC is approximately eighteen months. Chemotherapy is the mainstay of treatment while there is a growing body of evidence that targeted therapies may be on the horizon with poly-ADP-ribose polymerase (PARP) and immune check-point inhibitors already established in the treatment paradigm of TNBC. A large number of novel therapeutic agents are being evaluated for their efficacy in TNBC. As novel therapeutics are now incorporated into clinical practice, it is clear that tumor heterogeneity and clonal evolution can result to de novo or acquired treatment resistance. As precision medicine and next generation sequencing is part of cancer diagnostics, tailored treatment approaches based on the expression of molecular markers are currently being implemented in clinical practice and clinical trial design. The scope of this review is to highlight the most relevant current knowledge regarding underlying molecular profile of TNBC and its potential application in clinical practice.

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Section: Targeting Ar Pathwaymentioning

confidence: 76%

The Landscape of Targeted Therapies in TNBC

Vagia

Mahalingam

Cristofanilli

2020

Cancers

255

198

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“…This variation likely reflects different criteria defining an altered pathway, distinct assays and variant calling or differences in patient populations. The majority of our tumor samples were from metastatic sites (60.8%), while the entire METABRIC database and 82% of the PAKT samples were obtained from primary sites ( 38 , 39 ). The PAKT and the LOTUS trials enrolled patients with TNBC only ( 37 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

“…The majority of our tumor samples were from metastatic sites (60.8%), while the entire METABRIC database and 82% of the PAKT samples were obtained from primary sites ( 38 , 39 ). The PAKT and the LOTUS trials enrolled patients with TNBC only ( 37 , 38 ). In addition, there may also be racial and ethnic differences in the prevalence of PIK3CA-AKT1-PTEN alterations.…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer

et al. 2020

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Background: PI3K/AKT signaling pathway is activated in breast cancer and associated with cell survival. We explored the prevalence of PI3K pathway alterations and co-expression with other markers in breast cancer subtypes. Methods: Samples of non-matched primary and metastatic breast cancer submitted to a CLIA-certified genomics laboratory were molecularly profiled to identify pathogenic or presumed pathogenic mutations in the PIK3CA-AKT1-PTEN pathway using next generation sequencing. Cases with loss of PTEN by IHC were also included. The frequency of co-alterations was examined, including DNA damage response pathways and markers of response to immuno-oncology agents. Results: Of 4,895 tumors profiled, 3,558 (72.7%) had at least one alteration in the PIK3CA-AKT1-PTEN pathway: 1,472 (30.1%) harbored a PIK3CA mutation, 174 (3.6%) an AKT1 mutation, 2,682 (54.8%) had PTEN alterations ( PTEN mutation in 7.0% and/or PTEN loss by IHC in 51.4% of cases), 81 (1.7%) harbored a PIK3R1 mutation, and 4 (0.08%) a PIK3R2 mutation. Most of the cohort consisted of metastatic sites ( n = 2974, 60.8%), with PIK3CA mutation frequency increased in metastatic (32.1%) compared to primary sites (26.9%), p < 0.001. Other PIK3CA mutations were identified in 388 (7.9%) specimens, classified as “off-label,” as they were not included in the FDA-approved companion test for PIK3CA mutations. Notable co-alterations included increased PD-L1 expression and high tumor mutational burden in PIK3CA-AKT1-PTEN mutated cohorts. Novel concurrent mutations were identified including CDH1 mutations. Conclusions: Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for “off-label” PIK3CA mutations and combination strategies with potential clinical benefit for patients with breast cancer.

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“…Another actionable gene of PI3K/AKT/mTOR pathway is AKT1, and mutant AKT1 (ESCAT Tier IIB) was identi ed from 19 subjects, of which 15 were ER + with E17K being the most prevalent missense mutation [31]. In addition to capivasertib, a recent study showed that AKT1 E17K− mutant patients might bene t from mTOR inhibitor [32]. It deserves notice that the presence of AKT1 and PIK3CA variant was mutually exclusive (only 3 were mutated in both genes), and one plausible explanation comes from the fact that AKT1 is the downstream effector of PIK3CA.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive molecular profiling of Taiwanese breast cancers revealed potential therapeutic targets: prevalence of actionable mutations among 380 targeted sequencing analyses

Huang

Tsai

Liu

et al. 2020

Preprint

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IntroductionBreast cancer is one of the leading causes of cancer-related deaths in women, and the annual incidence of breast cancer has continuously increased throughout the past two decades in Taiwan. There is a demand in developing an Asian-based genetic profiling database for breast cancer in improving the treatment response and recurrence rate. This study aimed to determine molecular alternations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of Taiwanese breast cancers using a commercialized next-generation sequencing (NGS) target panel.Materials and methodsThe study population comprised a broad spectrum of breast cancer patients in Taiwan, including Group 1: planned to receive first-line surgery and followed by adjuvant therapy, or early relapse within three years, Group 2: planned to receive first-line neoadjuvant therapy and followed by surgery, and Group 3: de novo stage IV, or stage IV with recurrence beyond three years. Molecular profiles were determined using Thermo FisherTM OncomineTM Comprehensive Assay version 3 (TMO comprehensive assay) from Formalin-Fixed Paraffin-Embedded (FFPE) tissues. Level of actionability was evaluated with the ESMO Scale of clinical actionability of molecular targets (ESCAT).Results.A total of 380 TMO comprehensive assays were conducted on 372 patients, and we presented targeted sequencing analyses of Tier I: alteration-drug match associated with improved outcome in clinical trials including ERBB2 amplification, BRCA1/2 germline mutation, PIK3CA mutation, and NTRK translocation, and Tier II: antitumor activity associated with the matched alteration-drug but lack of prospective outcome data including PTEN loss, ESR1 mutation, AKT1 mutation, and ERBB2 mutation, and Tier III: matched drug-alteration that led to clinical beneﬁt in another tumor type including MDM2 amplification, and ERBB3 mutation. Among them, 249 (66%) showed at least one actionable alternation based on the ESCAT criteria. The most frequent impacted genes were PIK3CA (38%), followed by ERBB2 (23%), ESR1 (10%), AKT1 (6%), and BRCA2 (5%), and the remaining rare variants (less than 5% of assayed cohort) were BRCA1 (3%), MDM2 (2.2%), and ERBB3 (1.1%).ConclusionTargeted sequencing of actionable genes is believed to provide clinical applicability and substantial benefits for Taiwanese breast cancer patients. A valid scale of clinical actionability should be adopted for precision medicine practice under multidisciplinary molecular tumor board.

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Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial

Cited by 264 publications

References 26 publications

The Landscape of Targeted Therapies in TNBC

The Landscape of Targeted Therapies in TNBC

Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer

Comprehensive molecular profiling of Taiwanese breast cancers revealed potential therapeutic targets: prevalence of actionable mutations among 380 targeted sequencing analyses

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