Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor–Positive Metastatic Breast Cancer

Johnston, Stephen; Pippen, John; Pivot, Xavier; Lichinitser, Mikhail; Sadeghi, Saeed; Dièras, Véronique; Gómez, Henry L.; Romieu, Gilles; Manikhas, A.; Kennedy, M. John; Press, Michael F.; Maltzman, Julie; Florance, Allison; O’Rourke, Lisa; Oliva, Cristina; Stein, Steven; Pegram, Mark D.

doi:10.1200/jco.2009.23.3734

Cited by 955 publications

(672 citation statements)

References 35 publications

Supporting

Mentioning

635

Contrasting

Unclassified

Order By: Relevance

“…30,31 Recently, it has been shown that a combination of trastuzumab and hormonal therapy is superior than hormonal therapy alone. [32][33][34] However, the question of relative resistance to trastuzumab therapy in ER þ /HER2 þ tumors still remains. Whether this is because of ER and HER2 cross-talk only or other growth factor receptors are also involved is a subject of active investigation.…”

Section: Discussionmentioning

confidence: 99%

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

et al. 2011

View full text Add to dashboard Cite

Pathologic complete response to neoadjuvant chemotherapy without trastuzumab in hormone receptornegative/HER2 þ tumors is seen in 27-45% of cases. In contrast, estrogen receptor (ER) þ /HER2 þ tumors demonstrate pathologic complete response in B8% of cases and is generally limited to weak-to-moderate ER þ /HER2 þ tumors. It is speculated that addition of trastuzumab to neoadjuvant chemotherapy regimen will increase the pathologic complete response rates in all HER2 þ tumors. A list of HER2 þ patients who received neoadjuvant chemotherapy (with trastuzumab) in the years 2007-2010 was obtained from our hospital database. The 104 HER2 þ tumors were classified into three groups based on semiquantitative hormone receptor and HER2 results as follows: ERBB2 (ER-/PR-[H-score r10]/HER2 þ ), Luminal B-HER2 Hybrid (LBHH; weak to moderate ER þ [H-score 11-199]/HER2 þ ), and Luminal A-HER2 Hybrid (LAHH; strong ER þ [H-score Z200]/ HER2 þ ). Pathologic complete response was defined as absence of invasive carcinoma in the resection specimen and in the lymph nodes. Percentage tumor volume reduction was also calculated based on pretherapy size and detailed evaluation of the resection specimen. In all, 52% (25 of 48 cases) of ERBB2 tumors showed pathologic complete response, which was significantly higher than the pathologic complete response rate in LBHH (33%; 10 of 30) and LAHH (8%; 2 of 26) tumors. Average percentage tumor volume reduction was also highest in ERBB2 tumors (86%), followed by LBHH (74%) and LAHH (64%) tumors. We conclude that addition of trastuzumab to neoadjuvant chemotherapy regimen significantly increases the pathologic complete response rates in all HER2 þ tumors. However, the benefit of trastuzumab is highest in ER-negative tumors and progressively decreases with increase in tumor ER expression. This information can be utilized to counsel patients considered for neoadjuvant chemotherapy and the same principle could be applied in the adjuvant setting.

show abstract

Section: Discussionmentioning

confidence: 99%

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Breast cancer patients with oestrogen receptor-positive tumours revealing HER-2 amplification have been shown to respond poorly to endocrine therapy with aromatase inhibitors as well as tamoxifen. 147 Adding trastuzumab 148 or lapatinib 149 in concert improves response to aromatase inhibitors. The finding that mTOR inhibition may reverse resistance to endocrine agents in breast cancer MCF-7 cells 150,151 is consistent with clinical findings; recently, two studies reported addition of the mTOR inhibitor everolimus to endocrine therapy with the aromatase inhibitor exemestane 152 or the anti-oestrogen tamoxifen, 153 to significantly improve response to therapy in cancers nonamplified for HER-2.…”

Section: Activating Mutations In the Pten/pi3k/mtor Pathway As A Causmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

View full text Add to dashboard Cite

Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

show abstract

“…However, these approaches have shown limited efficacy; in fact, fulvestrant only elicits a response in approximately 7% of ERa-positive tumors that regrow under AI therapy, although its clinical use is justified based on a clinical benefit rate of 32% (Chia et al, 2008). On the other hand, trials with combinations of AIs and growth factor signal inhibitors have not improved outcomes in most cases , except for recent results on novel combinations that are still under research (Baselga et al, 2009;Johnston et al, 2009). In this scenario, the dynamic profiles of our model coincide with previous findings concerning the relevance of growth factor signaling but, importantly, our data also support a different explanation of the role of ERa: firstly, the switch from pS118-to pS167-ERa, an isoform known to be related to MAPK/AKT signaling (Campbell et al, 2001), may indicate that sustained ERa expression is more a consequence of the activation of other pro-growth signals than a reflection of the importance of canonical ERa function; secondly, the fact that both over-and underexpressed gene sets during MCF7-LTED adaptation showed infra representation of ERa-responsive elements and were not enriched in 17bE2-mediated regulation from original MCF7 data (Carroll et al, 2006), suggests a molecular landscape in which ERa, despite sustained expression, is no longer a highly active transcription modulator.…”

Section: Effect Of 17be2 Through Eramentioning

confidence: 99%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

View full text Add to dashboard Cite

Endocrine therapies targeting the proliferative effect of 17b-estradiol through estrogen receptor a (ERa) are the most effective systemic treatment of ERa-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The longterm estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERa. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERa transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERa were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERa-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

show abstract

Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor–Positive Metastatic Breast Cancer

Abstract: This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

Cited by 955 publications

References 35 publications

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Contact Info

Product

Resources

About