HER2 Support Group Forums - View Single Post - Combined ER and HER-targeted therapy in breast cancer treatment

Rich66 · 04-20-2009, 01:25 PM

Oncologist. 2010;15(2):122-9. Epub 2010 Feb 15.
Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer.

Schwarzberg LS, Franco SX, Florance A, O'Rourke L, Maltzman J, Johnston S.
The West Clinic, Memphis, Tennessee, USA.
Correspondence: Stephen R.D. Johnston, M.A., Ph.D., F.R.C.P., Royal Marsden NHS Foundation Trust & Institute of Cancer Research, Fulham Road, Chelsea, London, SW3 6JJ, United Kingdom. Telephone:44-0-20-7808-2748; Fax:44-0-20-7808-2563; e-mail: stephen.johnston@rmh.nhs.uk

FREE TEXT

Abstract

OBJECTIVE: To evaluate the efficacy and tolerability of letrozole plus lapatinib versus letrozole plus placebo in women with hormone receptor (HR)(+) human epidermal growth factor receptor (HER)-2(+) tumors receiving first-line therapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women (n = 1,286) with HR(+) MBC were randomized to daily oral treatment with letrozole (2.5 mg) plus lapatinib (1,500 mg) versus letrozole (2.5 mg) plus placebo. Of the 1,286 patients enrolled in the phase III study, 219 had HER-2(+) tumors. The primary endpoint was progression-free survival (PFS) in HER-2(+) patients. RESULTS: Results in the HR(+) HER-2(+) population (n = 219) are presented. The addition of lapatinib to letrozole resulted in a significantly lower risk for disease progression than with letrozole alone (hazard ratio, 0.71; 95% confidence interval, 0.53-0.96). The PFS time was 8.2 months, versus 3.0 months. The objective response rate (ORR) (28% versus 15%) and clinical benefit rate (CBR) (48% versus 29%) were also significantly greater in lapatinib-treated women. The most common adverse events in the lapatinib group were diarrhea (68%) and rash (46%), primarily grade 1 and 2. CONCLUSIONS: The addition of lapatinib to letrozole is well tolerated and leads to a significantly greater PFS time, ORR, and CBR than with letrozole alone in women with MBC who coexpress HR and HER-2.

PMID: 20156908 [PubMed - in process]

J Clin Oncol. 2009 Nov 20;27(33):5538-46. Epub 2009 Sep 28.
Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.

Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M.
Royal Marsden Hospital, London, United Kingdom. stephen.johnston@rmh.nhs.uk
Comment in:

J Clin Oncol. 2009 Nov 20;27(33):5492-4.

Abstract

PURPOSE: Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. CONCLUSION: 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.

PMID: 19786658 [PubMed - indexed for MEDLINE]

Thought: Faslodex with Herceptin/Tykerb?

[edit 1/3/10]
Ha! (update from SABC)

SABC 2009
[708] Different Mechanisms for Acquired Resistance to Trastuzumab and Lapatinib in HER2 Positive Breast Cancers: Role of ER and HER2 Reactivation.

Wang Y-C, Hennessy B, McAninch Ward R, Rimawi M, Huang C, Mills GB, Osborne CK, Schiff R Baylor College of Medicine, Houston, TX; M.D. Anderson, Houston, TX

About 25% of human breast cancers are amplified for HER2 with half of these tumors also expressing estrogen receptor (ER). Therapies targeting HER2 are very effective in the metastatic and the adjuvant settings, especially, although de novo or acquired resistance are still major problems. Trastuzumab (T) and lapatinib (L) are approved drugs now used in the clinic for treatment of HER2+ tumors. Data suggest that T works primarily by blocking signals generated by HER2 homodimers, while L is a small molecule tyrosine kinase inhibitor that more completely blocks the pathway by inhibiting HER1 in addition to HER2. In the clinic, these drugs demonstrate incomplete cross-resistance since L is active in some patients with T-resistant tumors. However, the mechanisms for this resistance have not been clarified.
To investigate the mechanisms for acquired resistance, we developed a panel of HER2+ cell lines resistant to T, L, and L+T by long-term exposure to increasing drug concentration in vitro. Two of these lines, BT474 and UACC812, are amplified for HER2 and also express ER, and they, together with subclones resistant to L, T, and L+T, were used to better understand potential resistance mechanisms. Western blot analysis of the parental BT474 and its resistant subclones showed that subclones resistant to T had reactivated the HER2 signaling pathway, while subclones resistant to L or L+T in which the HER receptor layer was more completely inhibited showed continued complete blockade of the HER2 pathway at the receptor layer but high levels of ER activity and phosphorylated-AKT. L, but not L+T, subclones after more prolonged time in culture did reactivate the HER pathway. UACC812 resistant cells were similar to BT474: T-resistant clones showed evidence of reactivation of HER signaling while L and L+T resistant clones showed enhanced ER activity. These cells showed no reactivation of HER signaling even after prolonged exposure in vitro. Consistent with these data, both BT474 and UACC812 T-resistant clones were still sensitive to and cell proliferation was inhibited by L. L-resistant clones, however, were also resistant to T. The potent anti-estrogen fulvestrant (F) was used to evaluate the role of ER in these resistant clones. T-resistant clones from both parental lines were resistant to F, indicating that ER had no role in resistance. In contrast, L and L+T-resistant clones, but not parental cells, were extremely sensitive to F with significant inhibition of cell proliferation in vitro.
These data demonstrate that only partial inhibition of the HER2 pathway in breast cancer cells by T can be overcome by activating other components of the HER pathway. Resistance to more complete HER2 blockade with L or L+T requires reactivation of a redundant cell survival pathway, in this case ER, which is upregulated by HER2 blockade. Optimal therapy in those tumors may require both ER and HER2-targeted therapy.

Saturday, December 12, 2009 7:00 AM

Carcinogenesis. 2010 Jan 12. [Epub ahead of print]
Genistein Induces Enhanced Growth Promotion in ER Positive/erbB-2 Overexpressing Breast Cancers by ER-erbB-2 crosstalk and p27/kip1 Downregulation.

Yang X, Yang S, McKimmey C, Liu B, Edgerton S, Bales W, Archer L, Thor AD.
Department of Pathology, University of Oklahoma Health Sciences Center.
Genistein is a major isoflavone with known hormonal and tyrosine kinase modulating activities. Genistein has been shown to promote the growth of estrogen receptor (ER) positive MCF-7 cells. In ER negative/erbB-2 overexpressing cells, genistein has been shown to inhibit cell growth through its tyrosine kinase inhibitor activity. The effects of genistein on cell growth and tamoxifen response in ER positive/erbB-2 altered breast cancers (known as luminal type B and noted in approximately 10-20% of breast cancers) have not been well explored. Using erbB-2 transfected ER+ MCF-7 cells, we found that genistein induced enhanced cellular proliferation and tamoxifen resistance when compared to control MCF-7 cells. These responses were accompanied by increased phosphorylation of ERalpha and ER signaling, without increase in ER protein levels. Genistein treated MCF-7/erbB-2 cells also showed enhanced activation/phosphorylation of erbB-2, Akt and MAPK/Erk. Blockade of the PI3K and/or MAPK pathways abrogated genistein induced growth promotion, suggesting that genistein effects involve both critical signaling pathways. We also found that p27/kip1 was markedly downregulated in genistein treated MCF-7/erbB-2 cells. Overexpression of p27/kip1 attenuated genistein mediated growth promotion.
In aggregate, our data suggest that the concomitant co-expression of ER and erbB-2 makes breast cancers particularly susceptible to the growth promoting effects of genistein across a wide range of doses. The underlying mechanisms involve enhanced ER-erbB-2 crosstalk and p27/kip1 downregulation.

PMID: 20067990 [PubMed - as supplied by publisher]

04-20-2009, 01:25 PM	#2
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Oncologist. 2010;15(2):122-9. Epub 2010 Feb 15. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Schwarzberg LS, Franco SX, Florance A, O'Rourke L, Maltzman J, Johnston S. The West Clinic, Memphis, Tennessee, USA. Correspondence: Stephen R.D. Johnston, M.A., Ph.D., F.R.C.P., Royal Marsden NHS Foundation Trust & Institute of Cancer Research, Fulham Road, Chelsea, London, SW3 6JJ, United Kingdom. Telephone:44-0-20-7808-2748; Fax:44-0-20-7808-2563; e-mail: stephen.johnston@rmh.nhs.uk FREE TEXT Abstract OBJECTIVE: To evaluate the efficacy and tolerability of letrozole plus lapatinib versus letrozole plus placebo in women with hormone receptor (HR)(+) human epidermal growth factor receptor (HER)-2(+) tumors receiving first-line therapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women (n = 1,286) with HR(+) MBC were randomized to daily oral treatment with letrozole (2.5 mg) plus lapatinib (1,500 mg) versus letrozole (2.5 mg) plus placebo. Of the 1,286 patients enrolled in the phase III study, 219 had HER-2(+) tumors. The primary endpoint was progression-free survival (PFS) in HER-2(+) patients. RESULTS: Results in the HR(+) HER-2(+) population (n = 219) are presented. The addition of lapatinib to letrozole resulted in a significantly lower risk for disease progression than with letrozole alone (hazard ratio, 0.71; 95% confidence interval, 0.53-0.96). The PFS time was 8.2 months, versus 3.0 months. The objective response rate (ORR) (28% versus 15%) and clinical benefit rate (CBR) (48% versus 29%) were also significantly greater in lapatinib-treated women. The most common adverse events in the lapatinib group were diarrhea (68%) and rash (46%), primarily grade 1 and 2. CONCLUSIONS: The addition of lapatinib to letrozole is well tolerated and leads to a significantly greater PFS time, ORR, and CBR than with letrozole alone in women with MBC who coexpress HR and HER-2. PMID: 20156908 [PubMed - in process] J Clin Oncol. 2009 Nov 20;27(33):5538-46. Epub 2009 Sep 28. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Royal Marsden Hospital, London, United Kingdom. stephen.johnston@rmh.nhs.uk Comment in: J Clin Oncol. 2009 Nov 20;27(33):5492-4. Abstract PURPOSE: Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. CONCLUSION: 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. PMID: 19786658 [PubMed - indexed for MEDLINE] Thought: Faslodex with Herceptin/Tykerb? [edit 1/3/10] Ha! (update from SABC) SABC 2009 [708] Different Mechanisms for Acquired Resistance to Trastuzumab and Lapatinib in HER2 Positive Breast Cancers: Role of ER and HER2 Reactivation. *Wang Y-C, Hennessy B, McAninch Ward R, Rimawi M, Huang C, Mills GB, Osborne CK, Schiff R Baylor College of Medicine, Houston, TX; M.D. Anderson, Houston, TX* About 25% of human breast cancers are amplified for HER2 with half of these tumors also expressing estrogen receptor (ER). Therapies targeting HER2 are very effective in the metastatic and the adjuvant settings, especially, although de novo or acquired resistance are still major problems. Trastuzumab (T) and lapatinib (L) are approved drugs now used in the clinic for treatment of HER2+ tumors. Data suggest that T works primarily by blocking signals generated by HER2 homodimers, while L is a small molecule tyrosine kinase inhibitor that more completely blocks the pathway by inhibiting HER1 in addition to HER2. In the clinic, these drugs demonstrate incomplete cross-resistance since L is active in some patients with T-resistant tumors. However, the mechanisms for this resistance have not been clarified. To investigate the mechanisms for acquired resistance, we developed a panel of HER2+ cell lines resistant to T, L, and L+T by long-term exposure to increasing drug concentration in vitro. Two of these lines, BT474 and UACC812, are amplified for HER2 and also express ER, and they, together with subclones resistant to L, T, and L+T, were used to better understand potential resistance mechanisms. Western blot analysis of the parental BT474 and its resistant subclones showed that subclones resistant to T had reactivated the HER2 signaling pathway, while subclones resistant to L or L+T in which the HER receptor layer was more completely inhibited showed continued complete blockade of the HER2 pathway at the receptor layer but high levels of ER activity and phosphorylated-AKT. L, but not L+T, subclones after more prolonged time in culture did reactivate the HER pathway. UACC812 resistant cells were similar to BT474: T-resistant clones showed evidence of reactivation of HER signaling while L and L+T resistant clones showed enhanced ER activity. These cells showed no reactivation of HER signaling even after prolonged exposure in vitro. Consistent with these data, both BT474 and UACC812 T-resistant clones were still sensitive to and cell proliferation was inhibited by L. L-resistant clones, however, were also resistant to T. The potent anti-estrogen fulvestrant (F) was used to evaluate the role of ER in these resistant clones. T-resistant clones from both parental lines were resistant to F, indicating that ER had no role in resistance. In contrast, L and L+T-resistant clones, but not parental cells, were extremely sensitive to F with significant inhibition of cell proliferation in vitro. These data demonstrate that only partial inhibition of the HER2 pathway in breast cancer cells by T can be overcome by activating other components of the HER pathway. Resistance to more complete HER2 blockade with L or L+T requires reactivation of a redundant cell survival pathway, in this case ER, which is upregulated by HER2 blockade. Optimal therapy in those tumors may require both ER and HER2-targeted therapy. Saturday, December 12, 2009 7:00 AM Carcinogenesis. 2010 Jan 12. [Epub ahead of print] Genistein Induces Enhanced Growth Promotion in ER Positive/erbB-2 Overexpressing Breast Cancers by ER-erbB-2 crosstalk and p27/kip1 Downregulation. Yang X, Yang S, McKimmey C, Liu B, Edgerton S, Bales W, Archer L, Thor AD. Department of Pathology, University of Oklahoma Health Sciences Center. Genistein is a major isoflavone with known hormonal and tyrosine kinase modulating activities. Genistein has been shown to promote the growth of estrogen receptor (ER) positive MCF-7 cells. In ER negative/erbB-2 overexpressing cells, genistein has been shown to inhibit cell growth through its tyrosine kinase inhibitor activity. The effects of genistein on cell growth and tamoxifen response in ER positive/erbB-2 altered breast cancers (known as luminal type B and noted in approximately 10-20% of breast cancers) have not been well explored. Using erbB-2 transfected ER+ MCF-7 cells, we found that genistein induced enhanced cellular proliferation and tamoxifen resistance when compared to control MCF-7 cells. These responses were accompanied by increased phosphorylation of ERalpha and ER signaling, without increase in ER protein levels. Genistein treated MCF-7/erbB-2 cells also showed enhanced activation/phosphorylation of erbB-2, Akt and MAPK/Erk. Blockade of the PI3K and/or MAPK pathways abrogated genistein induced growth promotion, suggesting that genistein effects involve both critical signaling pathways. We also found that p27/kip1 was markedly downregulated in genistein treated MCF-7/erbB-2 cells. Overexpression of p27/kip1 attenuated genistein mediated growth promotion. In aggregate, our data suggest that the concomitant co-expression of ER and erbB-2 makes breast cancers particularly susceptible to the growth promoting effects of genistein across a wide range of doses. The underlying mechanisms involve enhanced ER-erbB-2 crosstalk and p27/kip1 downregulation. PMID: 20067990 [PubMed - as supplied by publisher]