Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer

Tutt, Andrew N.J.; Robson, M.; Garber, Judy E.; Domchek, S. M.; Audeh, M. William; Weitzel, J. N.; Friedlander, M.; Carmichael, J.

doi:10.1200/jco.2009.27.18s.cra501

Cited by 53 publications

(30 citation statements)

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“…The drug was generally well tolerated with the most commonly reported grade 3 adverse events being fatigue, nausea, and vomiting. 54, 57 On the other hand, another study showed that olaparib had no activity in breast cancer outside of patients with known germline BRCA mutations, although epithelial ovarian cancer appears to respond similarly regardless of germline status. 58…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics of triple negative breast cancer in Egyptian women: a hospital-based experience

Gado

Ibrahim

Atef

et al. 2016

Int J Cancer Ther Oncol

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Purpose: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis despite the high rates of response to chemotherapy. We aim to study the clinical features, factors influencing recurrence and survival outcomes of TNBC patients. Methods: We retrospectively studied the charts of patients with biopsy proven TNBC treated at The Clinical Oncology Department Ain-Shams University between 2009 and 2012. Results: One hundred and forty five patients fulfilled the eligibility criteria. The incidence of TNBC was 10.5% -15% with a mean of 12% of all breast cancer patients. The follow-up duration ranged from six months to four years. The age range was 26 to 78 years. Infiltrating ductal carcinoma represented 93.1% of the pathologic types. 87% of patients were free of metastases (M0) at presentation. Clinical stages II and III represented 38 and 39.5% of the patients. 66% of patients had modified radical mastectomy. Following surgery, 77.5% of patients received adjuvant chemotherapy while 61% of the patients had adjuvant radiation therapy. Anthracyclines based chemotherapy was given to 52% of patients. Disease-free survival (DFS) of the M0 patients at 20 and 30 months was 92% and 80% respectively. Relapse occurred in 23% of M0 patients. After a mean duration of DFS of 15.1 months, the most common sites of metastases for relapsed M0 patients were pulmonary (44.8%), bone (41.4%), and locoregional (13.8%). The median overall survival (ORS) of patients was 18 months (1 -45 months), whereas for the M1 group of patients the median ORS was 9 months (2 -29 months). Conclusion: The incidence, pathological characteristics, and clinical behavior of TNBC were similar to what is mentioned in the literature. Adding taxanes to the chemotherapy protocols and using postoperative radiotherapy were both associated with a significant increase in the mean period of DFS, while did not significantly affect the ORS.

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Section: Discussionmentioning

confidence: 99%

Clinical characteristics of triple negative breast cancer in Egyptian women: a hospital-based experience

Gado

Ibrahim

Atef

et al. 2016

Int J Cancer Ther Oncol

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“…Olaparib deprives the tumor cells of another DNA repair mechanism, which seems to promote cancer cell death. 4…”

Section: Notable Advancesmentioning

confidence: 99%

Clinical Cancer Advances 2009: Major Research Advances in Cancer Treatment, Prevention, and Screening—A Report From the American Society of Clinical Oncology

Petrelli

Winer

Brahmer

et al. 2009

JCO

107

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A MESSAGE FROM ASCO'S PRESIDENT As this report demonstrates—and as history shows—investment in clinical cancer research pays off. Since 1990, cancer mortality rates have declined by 15%. Today, two thirds of patients survive at least 5 years after diagnosis, compared with just half of patients 40 years ago. Patient quality of life has improved dramatically. In addition, thanks to basic research advances, we are entering an era of personalized cancer medicine, in which treatment is tailored to the unique genetics of the individual. Clinical cancer research is finally receiving an urgently needed boost in investment. For the first time in 5 years, federal funding for research has increased. The economic stimulus package infused billions into short-term biomedical research projects, and President Obama has pledged to invest in “a cure for cancer in our time.” However, despite this progress, cancer remains the number-two killer of Americans. Incidence is projected to nearly double by 2020 as the population grows and ages. Scientifically, cancer is highly complex; it is not one disease, but many, and is increasingly defined by thousands of genetic variations, epigenetic changes, post-transcriptional modifications, and combinations of these mechanisms, rather than by site of origin. Unraveling these complexities begins to explain why some cancers are especially resistant to treatment, a fact we have known for some time. Other cancers are fatal because they are typically diagnosed late in the course of disease, when treatment is less effective. To achieve new breakthroughs, the scale of the national response must match the scale of the problem. Years of flat federal research funding have resulted in abandoned or stalled clinical research projects, a deteriorating research infrastructure, and the loss of talented physicians to other fields. In this report, the American Society of Clinical Oncology (ASCO) commends the recent increases in funding and calls on Congress to make a multiyear commitment to sustained increases in clinical cancer research at the National Institutes of Health and National Cancer Institute. Major advances in cancer treatment cannot be expected to emerge without consistent and predictable investment at the federal level. Although a robust clinical research enterprise is essential to improving patient care, advances mean little if they do not reach people in need. For people with cancer, lack of health insurance can be the difference between life and death. It is estimated that 32% of patients with cancer in the United States are uninsured at some point during their treatment, and more than a quarter opt not to seek treatment as a result. We must end the inequality in health care access. ASCO believes that health care reform must ensure that everyone diagnosed with cancer has the coverage necessary to receive high-quality treatment. To that end, we have made access to cancer care a top priority in our advocacy agenda. I believe the advances described in this report should give all of us cause for hope. Although there is a long road ahead, by investing in a robust national clinical research program and by improving access to high-quality care, we can give every patient the best chance of survival. Douglas Blayney, MD President American Society of Clinical Oncology

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“…The mechanism by which PARP inhibition can promote cell death in BRCA‐mutated cells is thought to be through synthetic lethality, defined as the co‐occurrence of multiple genetic events that results in organismal or cellular death (Lord et al, ). The PARP inhibitor Olaparib (AZD2281) is a small‐molecule that has shown efficacy in patients with germline BRCA mutations in clinical trials (Buege and Mahajan, ; Gelmon et al, ; Ledermann et al, ; Tutt et al, ). Olaparib was recently approved for use in late‐stage ovarian cancers with deleterious germline BRCA mutations as a result of its efficacy in clinical trials (Kim et al, ).…”

Section: Introductionmentioning

confidence: 99%

Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells

Decker

Hobson

Zhang

et al. 2017

Biotech & Bioengineering

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The development of resistance to targeted therapeutics is a challenging issue for the treatment of cancer. Cancers that have mutations in BRCA, a DNA repair protein, have been treated with poly (ADP-ribose) polymerase (PARP) inhibitors, which target a second DNA repair mechanism with the aim of inducing synthetic lethality. While these inhibitors have shown promise clinically, the development of resistance can limit their effectiveness as a therapy. This study investigated mechanisms of resistance in BRCA-mutated cancer cells (HCC1937) to Olaparib (AZD2281) using TRACER, a technique for measuring dynamics of transcription factor (TF) activity in living cells. TF activity was monitored in the parental HCC1937 cell line and two distinct resistant cell lines, one with restored wild-type BRCA1 and one with acquired resistance independent of BRCA1 for 48 hours during treatment with Olaparib. Partial least squares discriminant analysis (PLSDA) was used to categorize the three cell types based on TF activity, and network analysis was used to investigate the mechanism of early response to Olaparib in the study cells. NOTCH signaling was identified as a common pathway linked to resistance in both Olaparib-resistant cell types. Western blotting confirmed upregulation of NOTCH protein, and sensitivity to Olaparib was restored through co-treatment with a gamma secretase inhibitor. The identification of NOTCH signaling as a common pathway contributing to PARP inhibitor resistance by TRACER indicates the efficacy of transcription factor dynamics in identifying targets for intervention in treatment-resistant cancer and provides a new method for determining effective strategies for directed chemotherapy.

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Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer

Cited by 53 publications

References 0 publications

Clinical characteristics of triple negative breast cancer in Egyptian women: a hospital-based experience

Clinical characteristics of triple negative breast cancer in Egyptian women: a hospital-based experience

Clinical Cancer Advances 2009: Major Research Advances in Cancer Treatment, Prevention, and Screening—A Report From the American Society of Clinical Oncology

Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells

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