predicting resistance to herceptin therapy

[Lani]

I remember reading a thread started by someone whose breast cancer returned before they had even finished their herceptin treatment. I have previously given statistics quoted in the literature on how many her2+ patients respond vs. don't respond to herceptin given after chemo(usually quoted for patients with metastatic bc), and that, among those, the majority with become resistant within one year--again, don't panic. These numbers are quoted for Stage IV patients, and even for Stage IV patients I think the literature is lagging behind "facts on the ground" as evidenced by the many Stage IV posters here!

ANYWAY, here is a study where they looked at how resistance (do novo or acquired... I will be reading it in more detail) occurs. It had been noted that those with low PTEN values tended not to respond to herceptin de novo. But now it appears the PI3K pathway activation is the culprit. The good news--if that is the case, perhaps they could decide to treat patients differently upfront if they showed evidence of this problem, whether with Tykerb (unsure if the same would hold for them) or with combinations of herceptin with PI3K inhibitors they are working on, etc)

Lots more for me to read!!!

1: Cancer Cell. 2007 Oct;12(4):395-402.
A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer.

Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R.
Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy.
PMID: 17936563 [PubMed - in process]

[Lani]

1: Cancer Cell. 2007 Oct;12(4):297-9.
PI3 Kinase Activation and Response to Trastuzumab Therapy: What's neu with Herceptin Resistance?

Park BH, Davidson NE.
Breast Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Baltimore, MD 21231, USA.
Trastuzumab is an established therapy for women with breast cancers that overexpress HER2. Despite its proven benefit in treating breast cancer, not all women derive benefit from this monoclonal antibody, and resistant disease can develop. In this issue of Cancer Cell, Berns et al. present evidence that activation of the PI3 kinase pathway, either via loss of the tumor suppressor PTEN or through oncogenic stimulation of PIK3CA, can mediate trastuzumab resistance. This study extends important work of others and forms the rationale for future investigations combining inhibitors of the PI3 kinase pathway in conjunction with trastuzumab therapy.
PMID: 17936554 [PubMed - in process]

[Lani]

Genetic approach provides new insight into trastuzumab resistance in breast cancer [Eureka News Service]
A new study provides important insight into the mechanisms involved in resistance to treatment of breast cancer patients with trastuzumab (Herceptin). The research, published by Cell Press in the October issue of the journal Cancer Cell, identifies markers that may help to identify patients who are unlikely to respond to trastuzumab treatment and provides a potential strategy for treating these patients.
Trastuzumab is an antibody used as a therapy for patients whose breast cancers produce excess amounts of the protein HER2. However, almost half of these breast cancer patients are nonresponsive to trastuzumab therapy or become resistant during treatment. To better understand the antitumor activity of trastuzumab, Dr. Rene Bernards from The Netherlands Cancer Institute and his colleagues used a large-scale genome-wide RNA interference screen to search for genes involved in trastuzumab resistance in breast cancer.
The researchers identified only the tumor suppressor PTEN as a modulator of trastuzumab sensitivity in a breast cancer cell line. Earlier findings had associated PTEN with resistance to trastuzumab-based therapy, and loss of PTEN is known to result in hyperactivation of the PI3K pathway. Abnormal activation of this cell survival signaling pathway has been identified in many primary breast cancers. Hyperactivation of the PI3K pathway also can be caused by activating mutations of the PIK3CA gene.
"This finding, along with the high frequency of PIK3CA activating mutations in breast cancer, led us to investigate whether PI3K pathway activity, as assessed by cancer-associated activating mutations (of PIK3CA) or altered levels of PTEN, was able to predict trastuzumab resistance in the clinic," explains Dr. Bernards. This combined analysis identified twice as many patients at increased risk for disease progression as would analyzing PTEN alone and proved to be statistically significant as a biomarker for prognosis after trastuzumab therapy, indicating that assessment of PTEN expression together with PIK3CA mutation is required for optimal prediction of disease progression after trastuzumab therapy for breast cancer.
"Importantly, this study also illustrates the power of in vitro RNAi screens combined with confirmation on patient samples to identify biomarkers useful for predicting treatment response in the clinic," says Dr. Bernards. "It is too early to use these biomarkers; further validation studies are required before they can be used in the clinic. Nevertheless, it is likely that these findings will lead to a better understanding of resistance mechanisms and how to circumvent them as well as more reliable identification of the most effective treatment for individual patients."

[Lani]

Introduction

The mechanism by which trastuzumab exerts its antitumor activity is not fully understood. Trastuzumab has been suggested to induce antibody-dependent cellular cytotoxicity (ADCC) (Clynes et al., 2000), inhibit HER2 extracellular domain cleavage (Molina et al., 2001), or inhibit PI3K/AKT survival signaling, either by downregulating HER2 signaling (Yakes et al., 2002) or by increasing PTEN membrane localization and phosphatase activity, leading to a decline in PI3K/AKT pathway activation and inhibition of proliferation (Nagata et al., 2004). In addition, activation of HER-related receptors, such as HER3, or non-HER receptors, such as insulin-like growth factor I receptor, have been suggested in preclinical studies to increase PI3K/AKT signaling thereby limiting trastuzumab efficacy ([Lu et al., 2001] and [Sergina et al., 2007]). In spite of this, it is still largely unclear why almost half of the breast cancer patients that overexpress HER2 are initially nonresponsive to trastuzumab-based therapy even when combined with chemotherapy or eventually become resistant to trastuzumab during treatment ([Cobleigh et al., 1999], [Slamon et al., 2001] and [Vogel et al., 2002]). An understanding of the resistance mechanisms would stimulate the development of rational drug combinations to circumvent resistance and allow better selection of patients likely to respond.

[Jean]

Just bumping this post up....


jean