HER2 Support Group Forums - View Single Post - Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

Rich66 · 06-11-2009, 05:21 PM

Lapatinib May Target Breast Cancer Stem Cells

Zosia Chustecka

April 18, 2008 — Results from a small clinical trial of 45 patients with locally advanced breast cancer suggests that the novel agent lapatinib (Tykerb, GlaxoSmithKline) has an effect on tumor-causing breast cancer stem cells.
"We saw significant tumor regression after 6 weeks with single-agent lapatinib," Angel Rodriguez, MD, from the Baylor College of Medicine, in Houston, Texas, reported yesterday at the 6th European Breast Cancer Conference (EBCC) in Berlin, Germany.
Lapatinib is available in the United States but not yet in Europe. In the United States, lapatinib is indicated for use in combination with capecitabine in advanced or metastatic breast cancer overexpressing HER-2 in women who have already been treated with an anthracycline, a taxane, and trastuzumab. The drug is expected to be approved in Europe soon; the European Medicines Agency issued a positive opinion in December 2007 for use of the drug in advanced or metastatic HER-2 breast cancer.
In the current study, lapatinib was given at a much earlier disease stage than specified in its licensed indication. Dr. Rodriguez and colleagues used lapatinib in a neoadjuvant setting for locally advanced cancer, and gave the drug as a single agent for 6 weeks, followed by a combination of weekly trastuzumab and 3-weekly docetaxel for 12 weeks before primary surgery.
A core biopsy taken after the 6 weeks of lapatinib therapy showed significant tumor regression, the researchers reported. Bidimensional tumor measurements showed a median decrease of 60.8%. In addition, there was a decrease in the tumorigenic CD44+/CD24–/low breast cancer cells (considered to be stem cells), from 10.6% to 4.7%, and a reduced self-renewal capacity as measured by mammosphere formation assays (reduced from 30 to 15 mammosphere/10,000 cells; P = .01).
The researchers had previously found that the tumorigenic CD44+/CD24–/low cells were resistant to conventional chemotherapy. "Indeed, residual cancers that were exposed to such chemotherapy showed an increase in the tumor-causing cells and enhanced tumor initiation by the formation of mammospheres (small tumors that form when tumor-causing cells are cultured in a test tube), which reflect the capacity of the cells to self-renew. So we were excited to see that the results with lapatinib were different," Dr. Rodriguez commented in a statement.
Analysis of surgically removed tissue showed a pathological complete response rate of 63% (16/25) after lapatinib and trastuzumab/decetaxel therapy, a rate that was "much higher than expected," the researchers told the meeting.
"Contrary to conventional chemotherapy, human breast cancer specimens obtained from this prospective in vivo study have demonstrated for the first time that lapatinib decreases tumorigenic breast cancer stem cells in the primary breast cancers of women receiving neoadjuvant treatment," Dr. Rodriguez and colleagues concluded.
"This indicates that the stem cells themselves should be the specific target," Dr. Rodriguez commented, "rather than a broad-brush approach, in which cells are killed indiscriminately. Targeting the stem cells may be more effective and could also prevent some of the unpleasant side effects associated with conventional chemotherapy."
Asked to comment on these findings, Dr. Emiel Rutgers, MD, PhD, from the Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, in Amsterdam, who chaired the EBCC meeting, said: "If this is true — and it needs to be confirmed — then this is a bonus." The contention here is that such a response to just 6 weeks of lapatinib monotherapy — which wasn't expected — is due to the very basic and aggressive cancer stem cells being 'switched off'," he commented.
"However, one of the weak points in this research is that we talk about cancer stem cells, but we don't really know where they are," Dr. Rutgers told Medscape Oncology in an interview. "There is a lot of work supporting this concept, but if you ask me where the stem cell is in a tumor, well that's not so easy.... It's all conceptual. But it's a nice concept and a lot of research fits in with this concept, so there must be something true in it."
The response seen to lapatinib alone bodes well for the ongoing ALTTO study involving 8000 women, Dr. Rutgers commented. This study is comparing lapatinib with trastuzumab (Herceptin, Roche), both together and alone, in the adjuvant setting. However, the group in this study that involves monotherapy with lapatinib has been criticized, and some doctors have been reluctant to recruit women into this trial because they believe that there isn't enough evidence that lapatinib alone is effective. "So this latest bit of information will really help us to go forward with the ALTTO trial," Dr. Rutgers said.
6th European Breast Cancer Conference (EBCC): Abstract 204. Presented April 17, 2008.

http://alttotrials.com/patients.php#5

Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment.

Camara O, Jörke C, Hammer U, Egbe A, Rabenstein C, Runnebaum IB, Hoeffken K, Pachmann K.
Women's Hospital, Friedrich Schiller University, Bachstr. 18, 07740, Jena, Germany.
BACKGROUND: In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse. METHOD: In this study, CETC were monitored using the Maintrac method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib. RESULTS: In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease. CONCLUSIONS: In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies.

PMID: 18936973 [PubMed - indexed for MEDLINE]

06-11-2009, 05:21 PM	#17
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Lapatinib May Target Breast Cancer Stem Cells Zosia Chustecka April 18, 2008 — Results from a small clinical trial of 45 patients with locally advanced breast cancer suggests that the novel agent lapatinib (Tykerb, GlaxoSmithKline) has an effect on tumor-causing breast cancer stem cells. "We saw significant tumor regression after 6 weeks with single-agent lapatinib," Angel Rodriguez, MD, from the Baylor College of Medicine, in Houston, Texas, reported yesterday at the 6th European Breast Cancer Conference (EBCC) in Berlin, Germany. Lapatinib is available in the United States but not yet in Europe. In the United States, lapatinib is indicated for use in combination with capecitabine in advanced or metastatic breast cancer overexpressing HER-2 in women who have already been treated with an anthracycline, a taxane, and trastuzumab. The drug is expected to be approved in Europe soon; the European Medicines Agency issued a positive opinion in December 2007 for use of the drug in advanced or metastatic HER-2 breast cancer. In the current study, lapatinib was given at a much earlier disease stage than specified in its licensed indication. Dr. Rodriguez and colleagues used lapatinib in a neoadjuvant setting for locally advanced cancer, and gave the drug as a single agent for 6 weeks, followed by a combination of weekly trastuzumab and 3-weekly docetaxel for 12 weeks before primary surgery. A core biopsy taken after the 6 weeks of lapatinib therapy showed significant tumor regression, the researchers reported. Bidimensional tumor measurements showed a median decrease of 60.8%. In addition, there was a decrease in the tumorigenic CD44+/CD24–/low breast cancer cells (considered to be stem cells), from 10.6% to 4.7%, and a reduced self-renewal capacity as measured by mammosphere formation assays (reduced from 30 to 15 mammosphere/10,000 cells; P = .01). The researchers had previously found that the tumorigenic CD44+/CD24–/low cells were resistant to conventional chemotherapy. "Indeed, residual cancers that were exposed to such chemotherapy showed an increase in the tumor-causing cells and enhanced tumor initiation by the formation of mammospheres (small tumors that form when tumor-causing cells are cultured in a test tube), which reflect the capacity of the cells to self-renew. So we were excited to see that the results with lapatinib were different," Dr. Rodriguez commented in a statement. Analysis of surgically removed tissue showed a pathological complete response rate of 63% (16/25) after lapatinib and trastuzumab/decetaxel therapy, a rate that was "much higher than expected," the researchers told the meeting. "Contrary to conventional chemotherapy, human breast cancer specimens obtained from this prospective in vivo study have demonstrated for the first time that lapatinib decreases tumorigenic breast cancer stem cells in the primary breast cancers of women receiving neoadjuvant treatment," Dr. Rodriguez and colleagues concluded. "This indicates that the stem cells themselves should be the specific target," Dr. Rodriguez commented, "rather than a broad-brush approach, in which cells are killed indiscriminately. Targeting the stem cells may be more effective and could also prevent some of the unpleasant side effects associated with conventional chemotherapy." Asked to comment on these findings, Dr. Emiel Rutgers, MD, PhD, from the Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, in Amsterdam, who chaired the EBCC meeting, said: "If this is true — and it needs to be confirmed — then this is a bonus." The contention here is that such a response to just 6 weeks of lapatinib monotherapy — which wasn't expected — is due to the very basic and aggressive cancer stem cells being 'switched off'," he commented. "However, one of the weak points in this research is that we talk about cancer stem cells, but we don't really know where they are," Dr. Rutgers told Medscape Oncology in an interview. "There is a lot of work supporting this concept, but if you ask me where the stem cell is in a tumor, well that's not so easy.... It's all conceptual. But it's a nice concept and a lot of research fits in with this concept, so there must be something true in it." The response seen to lapatinib alone bodes well for the ongoing ALTTO study involving 8000 women, Dr. Rutgers commented. This study is comparing lapatinib with trastuzumab (Herceptin, Roche), both together and alone, in the adjuvant setting. However, the group in this study that involves monotherapy with lapatinib has been criticized, and some doctors have been reluctant to recruit women into this trial because they believe that there isn't enough evidence that lapatinib alone is effective. "So this latest bit of information will really help us to go forward with the ALTTO trial," Dr. Rutgers said. 6th European Breast Cancer Conference (EBCC): Abstract 204. Presented April 17, 2008. http://alttotrials.com/patients.php#5 Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment. Camara O, Jörke C, Hammer U, Egbe A, Rabenstein C, Runnebaum IB, Hoeffken K, Pachmann K. Women's Hospital, Friedrich Schiller University, Bachstr. 18, 07740, Jena, Germany. BACKGROUND: In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse. METHOD: In this study, CETC were monitored using the Maintrac method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib. RESULTS: In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease. CONCLUSIONS: In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies. PMID: 18936973 [PubMed - indexed for MEDLINE]