PI3KCA mutations and/or PTEN loss in Her2-positive breast carcinomas treated with trastuzumab are not related to resistance to anti-Her2 therapy

Barbareschi, Mattia; Cuorvo, Lucia Veronica; Girlando, Salvatore; Bragantini, Emma; Eccher, Claudio; Leonardi, Elena; Ferro, Antonella; Caldara, A.; Triolo, R; Cantaloni, Chiara; Decarli, Nicola; Galligioni, Enzo; Palma, Paolo Dalla

doi:10.1007/s00428-012-1267-2

Cited by 24 publications

(23 citation statements)

References 40 publications

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“…After exclusion of duplicate references, nonrelevant literature, and those that did not satisfy the inclusion criteria, 19 candidate articles were included. AHT was used for advanced breast cancer in eight studies [13][14][15][16][17][18][19][20], in eight studies in the neoadjuvant setting [21][22][23][24][25][26][27][28], in two adjuvant trials [29,30], and in one study in both metastatic and neoadjuvant disease [31]. Tables 1, 2, 3, 4, 5 and 6 outline the main study characterizes and the outcomes of the 19 included studies.…”

Section: Resultsmentioning

confidence: 99%

“…AHT was combined with taxenes in three studies [16,19,31], while no chemotherapy was used in two studies [14,18] and in one arm in a third study [15]. Table 2 shows that five studies reported on objective response rate (ORR) of WT versus MT subgroups [13,14,[18][19][20]31], while five studies reported survival outcomes [15-17, 19, 20]. Table 3 shows that there were 828 patients with early stage breast cancer, 671 (81 %) and 157 (19 %) patients had WT and MT PIK3CA tumors, respectively.…”

Section: Studies In Metastatic Diseasementioning

confidence: 99%

“…When reported, the median (95 % CI) of the follow-up was 45 (37-57) months. In five studies including the GeparQuattro trial, a single AHT was used [23,31], while in the remaining six studies (including GeparQuinto and GeparSixto studies), either a single AHT or dual agents were used.…”

Section: Studies In the Neoadjuvant Settingmentioning

confidence: 99%

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The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis

Ibrahim

Kazkaz

Al‐Μansour³

et al. 2015

Breast Cancer Res Treat

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The association between PIK3CA mutation and resistance to anti-HER2 therapy (AHT) is not precisely defined. This meta-analysis intended to explore the clinical utility of PIK3CA mutation in HER2-positive breast cancer treated with AHT. Literature search identified 19 eligible studies. There were 1720 patients with advanced, 828 with early and 1290 patients treated in the neoadjuvant setting. In metastatic breast cancer, AHT showed no differential objective response benefit between the wild type (WT) and the mutated type (MT) PIK3CA subgroups (odds ratio [OR] = 1.09; 95 % CI 0.60-2.00; P = 0.78). AHT favorable affected progression-free survival (PFS) irrespective of PIK3CA mutation. There was no PFS difference between WT and MT regardless of the offered therapy. In early breast cancer, trastuzumab combined with the same chemotherapy conferred consistent relapse-free survival benefit in WT and MT subgroups (WT: HR = 0.59; 95 % CI 0.44-0.80; P < 0.001 vs. MT: HR = 0.42; 95 % CI 0.24-0.74; P < 0.001). In the neoadjuvant setting, AHT-based therapy produced a 72 % higher pathologic complete response (pCR) rate in WT as compared with that in MT PIK3CA tumors (OR = 1.72; 95 % CI 1.29-2.13; P < 0.001). In that setting, there was no disease-free or overall survival difference based on PIK3CA mutational status. In this meta-analysis, AHT did not achieve differential benefit according to PIK3CA mutation in HER2-positive metastatic or early breast cancer; however, in the neoadjuvant setting, patients harboring WT PIK3CA tumors attained a higher pCR rate.

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Section: Resultsmentioning

confidence: 99%

Section: Studies In Metastatic Diseasementioning

confidence: 99%

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The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis

Ibrahim

Kazkaz

Al‐Μansour³

et al. 2015

Breast Cancer Res Treat

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“…As trastuzumab, T-DM1 suppresses the phosphatidylinositol 3′-kinase (PI3K) signaling pathway [40]. The potential association between PIK3CA mutational status and T-DM1 efficacy remains unknown, but the results from clinical breast cancer series suggest that trastuzumab benefit does not depend on the mutational status of PIK3CA [55,56] or tumor PTEN expression [57]. …”

Section: Resistance To T-dm1mentioning

confidence: 99%

Trastuzumab emtansine: mechanisms of action and drug resistance

2014

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Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced breast cancer. T-DM1 is currently being evaluated as adjuvant treatment for early breast cancer. It has several mechanisms of action consisting of the anti-tumor effects of trastuzumab and those of DM1, a cytotoxic anti-microtubule agent released within the target cells upon degradation of the human epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. The cytotoxic effect of T-DM1 likely varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to T-DM1. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance. The mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of trastuzumab to cancer cells may be involved. The cytotoxic effect of T-DM1 may be impaired by inefficient internalization or enhanced recycling of the HER2-T-DM1 complex in cancer cells, or impaired lysosomal degradation of trastuzumab or intracellular trafficking of HER2. The effect of T-DM1 may also be compromised by multidrug resistance proteins that pump DM1 out of cancer cells. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations of T-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1.

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“…Potential molecular mechanisms of trastuzumab resistance in these patient groups were evaluated in several studies. Furthermore, many studies exploring potential prognostic factors to identify clinical determinants have failed to reach a definitive conclusion [10,11]. In our study, we examined prognostic factors affecting the recurrence-free survival (RFS) in patients with HER2-positive EBC treated with 52 weeks of adjuvant trastuzumab.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Factors for Recurrence-Free Survival in Patients with HER2-Positive Early-Stage Breast Cancer Treated with Adjuvant Trastuzumab

et al. 2013

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Background: The objective of this study was to identify prognostic factors affecting the recurrence-free survival (RFS) in patients who received a 52-week trastuzumab therapy for HER2-positive early stage breast cancer (EBC). Patients and Methods: The medical records of all patients with EBC from 10 centers were analyzed. Pathologic and clinical tumor characteristics were evaluated in 424 female patients who received 52 weeks of adjuvant trastuzumab for HER2-positive EBC. Survival was estimated using the Kaplan-Meier method. Univariate analyses of RFS were performed with the log-rank test. Independent prognostic and predictive factors affecting RFS were assessed by Cox regression analysis. Results: Median follow-up time was 33.1 months (range 9.2-75.9 months). 3-year RFS and overall survival were 87 and 97%, respectively. In multivariate analysis, patients aged 70 years or over (p = 0.017, relative risk (RR) 2.7, 95% confidence interval (CI) 1.19-6.13), patients with > 9 positive lymph nodes (p = 0.001, RR 2.52, 95% CI 1.42-4.46), and those with progesterone receptor-negative tumors (p = 0.006, RR 2.33, 95% CI 1.27-4.27) had worse RFS. Conclusion: In spite of a 52-week adjuvant trastuzumab treatment, classic poor prognostic factors for invasive EBC remained as such in patients with HER2-positive EBC.

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PI3KCA mutations and/or PTEN loss in Her2-positive breast carcinomas treated with trastuzumab are not related to resistance to anti-Her2 therapy

Cited by 24 publications

References 40 publications

The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis

The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis

Trastuzumab emtansine: mechanisms of action and drug resistance

Prognostic Factors for Recurrence-Free Survival in Patients with HER2-Positive Early-Stage Breast Cancer Treated with Adjuvant Trastuzumab

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