"Negative" Data -- What To Do With Them?
"Negative" Data -- What To Do With Them?
Large-scale clinical trials are designed to test efficacy of new agents or new regimens on the basis of preliminary observations obtained in preclinical and in phase 1/2 studies, in the hope to improve quality of care. Yet, expectations are not always met. Agents or regimens expected to be highly effective do not hold their promise and show only slightly better outcomes or no improvement at all vs the accepted standard of care. What should the oncology community, the medical journals, and the press in general do with these "negative" results? Forget about them and move on? Or analyze them carefully, discuss them at specialty meetings, and publish them when enough data are available? True, like reading about bad news, listening to "negative" data may be disheartening, and appear, sometimes, to be a waste of time. But is it indeed so?
Two of the 3 presentations chosen for the plenary session at the 27th Congress of the European Society of Medical Oncology (ESMO) contained only "negative" data. One more study in a long string of trials showed lack of benefit from high-dose chemotherapy in breast cancer patients, and the phase 3 data obtained with the EGFR tyrosine kinase inhibitor ZD1839 combined with 2 different chemotherapy regimens in nonsmall-cell lung cancer patients did not confirm the high expectations raised by two phase 2 studies.
Concerns about the biased release of data -- only the "positive" ones reach the surface -- expressed more and more frequently in the past few years by clinical researchers and medical editors, have been voiced once more in Nice at the debate session on treatment of metastatic breast cancer. What happens if only the first "positive" trial is published and the following 3 or 4 "negative" studies are "forgotten" in a drawer?
Oncologists, as all physicians, need to know what works and what doesn't work to make meaningful decisions on the basis of available evidence. If the design and purpose of a trial was thought important enough to enroll and treat hundreds or thousands of patients, then the ensuing data are important enough to be presented and published, even in the face of disappointing results. Clinical researchers, industry supporters, conference organizers, and medical editors and reviewers all share the responsibility to make all meaningful information available to the community at large in the most suitable way.
Our CME coverage of the 27th ESMO Congress will soon be posted. In the meantime, you can peruse through our collection of news highlights.
In the latest issue of Nature Medicine, 3 groups of researchers reported the identification of another intracellular pathway that might be critically involved in the development and/or maintenance of breast cancer growth. On our site, we post one of these articles in its entirety, by Liang and colleagues, that provides most of the clinical data available so far. As shown also by Viglietto's and Slingerland's groups, the intracellular signaling molecule p27 upon phosphorylation is sequestered in the cytoplasm of breast cancer cells and thus unable to bind and inhibit cdk2, a nuclear protein critically involved in cell cycle regulation. Unrestricted cdk2, in turn, can activate EF2 and allow uncontrolled cell proliferation. The kinase responsible for the phosphorylation and cytoplasmic sequestration of p27 was identified as Akt/PKB, a mediator of oncogenic signals delivered through the mitogen-activated EGF and HER2 receptors. Consistently with this model, in tumors with activated Akt, p27 was found to be phosphorylated and mostly cytoplasmic.
Of note, analysis of 128 breast cancer cases showed that patients with high levels and nuclear localization of p27 seemed to fare better in terms of disease-free and overall survival than patients with low p27 and cytoplasmic localization. As pointed out in the accompanying News and Views by Blain and Massagué, p27 may then be viewed not only as a new prognostic factor for breast cancer, but also as a tumor suppressor protein. Therapeutic manipulation of the Akt kinase upstream of p27 may represent a new target for the development of anticancer treatments. Analysis of a higher number of tumors and patients will help to better define the prognostic value of phosphorylated p27 and its potential inclusion in routine evaluation of breast cancer specimens.
If you have any comments, questions, or suggestions, please write to: HemOncEditor@webmd.net. If your concern is technical, contact our customer support staff at: medscapecustomersupport@webmd.net.
Large-scale clinical trials are designed to test efficacy of new agents or new regimens on the basis of preliminary observations obtained in preclinical and in phase 1/2 studies, in the hope to improve quality of care. Yet, expectations are not always met. Agents or regimens expected to be highly effective do not hold their promise and show only slightly better outcomes or no improvement at all vs the accepted standard of care. What should the oncology community, the medical journals, and the press in general do with these "negative" results? Forget about them and move on? Or analyze them carefully, discuss them at specialty meetings, and publish them when enough data are available? True, like reading about bad news, listening to "negative" data may be disheartening, and appear, sometimes, to be a waste of time. But is it indeed so?
Two of the 3 presentations chosen for the plenary session at the 27th Congress of the European Society of Medical Oncology (ESMO) contained only "negative" data. One more study in a long string of trials showed lack of benefit from high-dose chemotherapy in breast cancer patients, and the phase 3 data obtained with the EGFR tyrosine kinase inhibitor ZD1839 combined with 2 different chemotherapy regimens in nonsmall-cell lung cancer patients did not confirm the high expectations raised by two phase 2 studies.
Concerns about the biased release of data -- only the "positive" ones reach the surface -- expressed more and more frequently in the past few years by clinical researchers and medical editors, have been voiced once more in Nice at the debate session on treatment of metastatic breast cancer. What happens if only the first "positive" trial is published and the following 3 or 4 "negative" studies are "forgotten" in a drawer?
Oncologists, as all physicians, need to know what works and what doesn't work to make meaningful decisions on the basis of available evidence. If the design and purpose of a trial was thought important enough to enroll and treat hundreds or thousands of patients, then the ensuing data are important enough to be presented and published, even in the face of disappointing results. Clinical researchers, industry supporters, conference organizers, and medical editors and reviewers all share the responsibility to make all meaningful information available to the community at large in the most suitable way.
Our CME coverage of the 27th ESMO Congress will soon be posted. In the meantime, you can peruse through our collection of news highlights.
In the latest issue of Nature Medicine, 3 groups of researchers reported the identification of another intracellular pathway that might be critically involved in the development and/or maintenance of breast cancer growth. On our site, we post one of these articles in its entirety, by Liang and colleagues, that provides most of the clinical data available so far. As shown also by Viglietto's and Slingerland's groups, the intracellular signaling molecule p27 upon phosphorylation is sequestered in the cytoplasm of breast cancer cells and thus unable to bind and inhibit cdk2, a nuclear protein critically involved in cell cycle regulation. Unrestricted cdk2, in turn, can activate EF2 and allow uncontrolled cell proliferation. The kinase responsible for the phosphorylation and cytoplasmic sequestration of p27 was identified as Akt/PKB, a mediator of oncogenic signals delivered through the mitogen-activated EGF and HER2 receptors. Consistently with this model, in tumors with activated Akt, p27 was found to be phosphorylated and mostly cytoplasmic.
Of note, analysis of 128 breast cancer cases showed that patients with high levels and nuclear localization of p27 seemed to fare better in terms of disease-free and overall survival than patients with low p27 and cytoplasmic localization. As pointed out in the accompanying News and Views by Blain and Massagué, p27 may then be viewed not only as a new prognostic factor for breast cancer, but also as a tumor suppressor protein. Therapeutic manipulation of the Akt kinase upstream of p27 may represent a new target for the development of anticancer treatments. Analysis of a higher number of tumors and patients will help to better define the prognostic value of phosphorylated p27 and its potential inclusion in routine evaluation of breast cancer specimens.
If you have any comments, questions, or suggestions, please write to: HemOncEditor@webmd.net. If your concern is technical, contact our customer support staff at: medscapecustomersupport@webmd.net.
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