Clinical and genomic analysis of a randomised phase II study evaluating anastrozole and fulvestrant in postmenopausal patients treated for large operable or locally advanced hormone-receptor-positive breast cancer

Quénel-Tueux, Nathalie; Debled, Marc; Rudewicz, Justine; MacGrogan, Gaëtan; Pulido, Marina; Mauriac, L.; Dalenc, Florence; Bachelot, Thomas; Lortal, Barbara; Breton-Callu, C.; Madranges, Nicolas; Lara, C. Tunon de; Fournier, Marion; Bonnefoi, Hervé; Soueidan, Hayssam; Nikolski, Macha; Gros, Audrey; Daly, Catherine; Wood, Henry M.; Rabbitts, Pamela; Iggo, Richard

doi:10.1038/bjc.2015.247

Cited by 24 publications

(20 citation statements)

References 39 publications

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“…Reduced heterogeneity was found after 6 months of AI treatment17. In our data, after much shorter time, we found that the number of mutations and the VAFs were slightly but statistically significantly lower in the surgical samples of treated compared with control patients, possibly indicating a modest treatment effect.…”

Section: Discussionsupporting

confidence: 40%

Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

et al. 2016

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Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

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Section: Discussionsupporting

confidence: 40%

Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

et al. 2016

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“…Results demonstrated no significant difference in tumor response by ultrasonography in the intent-to-treat population (OR, 1.30; 95% CI, 0.64–2.64; P = .47) but higher biological activity for the 500-mg vs the 250-mg doses, consistent with observations in the metastatic setting. Our updated search revealed 1 study 29 that compared neoadjuvant anastrozole with fulvestrant, which showed similar response rates (33 of 56 [58.9%] vs 28 of 52 [53.8%], respectively) and BCS rates (33 of 56 [58.9%] vs 26 of 52 [50.0%], respectively).…”

Section: Resultsmentioning

confidence: 99%

Neoadjuvant Endocrine Therapy for Estrogen Receptor–Positive Breast Cancer

et al. 2016

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IMPORTANCE Estrogen receptor-positive (ER+) tumors of the breast are generally highly responsive to endocrine treatment. Although endocrine therapy is the mainstay of adjuvant treatment for ER+ breast cancer, the role of endocrine therapy in the neoadjuvant setting is unclear. OBJECTIVE To evaluate the effect of neoadjuvant endocrine therapy (NET) on the response rate and the rate of breast conservation surgery (BCS) for ER+ breast cancer. DATA SOURCES Based on PRISMA guidelines, a librarian-led search of PubMed and Ovid MEDLINE was performed to identify eligible trials published from inception to May 15, 2015. The search was performed in May 2015. STUDY SELECTION Inclusion criteria were prospective, randomized, neoadjuvant clinical trials that reported response rates with at least 1 arm incorporating NET (n = 20). Two authors independently analyzed the studies for inclusion. DATA EXTRACTION AND SYNTHESIS Pooled odds ratios (ORs), 95% CIs, and P values were estimated for end points using the fixed- and random-effects statistical model. RESULTS The analysis included 20 studies with 3490 unique patients. Compared with combination chemotherapy, NET as monotherapy with aromatase inhibitors had a similar clinical response rate (OR, 1.08; 95% CI, 0.50–2.35; P = .85; n = 378), radiological response rate (OR, 1.38; 95% CI, 0.92–2.07; P = .12; n = 378), and BCS rate (OR, 0.65; 95% CI, 0.41–1.03; P = .07; n = 334) but with lower toxicity. Aromatase inhibitors were associated with a significantly higher clinical response rate (OR, 1.69; 95% CI, 1.36–2.10; P < .001; n = 1352), radiological response rate (OR, 1.49; 95% CI, 1.18–1.89; P < .001; n = 1418), and BCS rate (OR, 1.62; 95% CI, 1.24–2.12; P < .001; n = 918) compared with tamoxifen. Dual combination therapy with growth factor pathway inhibitors was associated with a higher radiological response rate (OR, 1.59; 95% CI, 1.04–2.43; P = .03; n = 355), but not clinical response rate (OR, 0.76; 95% CI, 0.54–1.07; P = .11; n = 537), compared with endocrine monotherapy. The incidence of pathologic complete response was low (<10%). CONCLUSIONS AND RELEVANCE Neoadjuvant endocrine therapy, even as monotherapy, is associated with similar response rates as neoadjuvant combination chemotherapy but with significantly lower toxicity, suggesting that NET needs to be reconsidered as a potential option in the appropriate setting. Additional research is needed to develop rational NET combinations and predictive biomarkers to personalize the optimal neoadjuvant strategy for ER+ breast cancer.

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“…We observed FOXA1-CNG and amplification in 20% of the TCGA breast tumors, with a broader FOXA1-CNG distribution in the luminal B subtype. In a recent study reporting genomic profiling of clinical samples, about one-third (7/20) of the ER + residual disease showed CN changes after 6 mo of neoadjuvant anastrozole or Ful treatment (46). Interestingly, compared with the baseline tumors, focal amplicons involving the FOXA1 or ESR1 gene appeared in two separate cases in the anastrozole arm, supporting clonal selection by the treatment in a subgroup of patients as a mechanism to compensate or overcome the inhibition of the clinical target/pathway.…”

Section: Discussionmentioning

confidence: 99%

FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer

Jeselsohn

Pereira

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

122

120

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Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors. A bout 75% of breast cancers express estrogen receptor α (ER), which is a strong driver and therapeutic target for these ER-positive ( + ) tumors. Endocrine therapy with aromatase inhibitors lowers the level of estrogen; selective ER modulators such as tamoxifen (Tam) bind to and block ER, and down-regulators such as fulvestrant (Ful) bind to ER and induce its degradation. Endocrine therapy prolongs disease-free and overall survival when used in the adjuvant setting and can induce long-term remission in some patients in the metastatic setting. Despite the overall success of endocrine therapy, tumors in more than 50% of patients with metastatic disease fail to respond, and nearly all metastatic patients with initially responding tumors eventually experience tumor relapse and die from acquired resistance (1, 2). Although there are many causes for resistance, the most predominant mechanisms include altered ER signaling and interactions between ER, its coregulators, and various growth factor pathways. These alterations facilitate adaptation from ligand-dependent to ligand-independent ER activation, which is further triggered by cross-talk with growth factor receptor (GFR) signaling pathways (3-6). However, the key mediators of ER transcriptional reprogramming in promoting endocrineresistant (Endo-R) breast cancer remain poorly understood.Recently, a potential role of the forkhead box protein A1 (FOXA1) has been suggested in mediating endocrine resistance in breast cancer (7,8). FOXA1 is termed a "pioneer factor" because it binds to highly compacted or "closed" chromatin via a domain similar to that of linker histones and, through its C-terminal domain, renders these genomic regions more accessible to other transcription factors, such as ER (9), progesterone receptor (PR) (10), and androgen receptor (AR) (11). As such, FOXA1 has a key role in demarcating the tissue-specific binding sites of these nuclear receptors (12). Together with ER, FOXA1 contributes to the pattern of gene transcription that induces luminal cell differentiation (13) and represses the basal phenotype (14). Like E...

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Clinical and genomic analysis of a randomised phase II study evaluating anastrozole and fulvestrant in postmenopausal patients treated for large operable or locally advanced hormone-receptor-positive breast cancer

Cited by 24 publications

References 39 publications

Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

Neoadjuvant Endocrine Therapy for Estrogen Receptor–Positive Breast Cancer

FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer

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