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Modified resistance to chemotherapy and trastuzumab by bevacizumab in locally recurrent breast cancer
The Breast 18 (2009) 66–68
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Short Report
Modified resistance to chemotherapy and trastuzumab by bevacizumab in locally recurrent breast cancer Mirna H. Farhat, Nagi S. El-Saghir, Ali I. Shamseddine* American University of Beirut-Medical center, Internal medicine-Division of Hematology-Oncology, P.O. Box: 11-0236/E21-Tumor registry, Riad El – Solh 11070720, Beirut-Lebanon
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 April 2007 Received in revised form 9 September 2008 Accepted 25 September 2008
Antiangiogenic therapy is a valuable new approach in the treatment of breast cancer. Response rates ranging from 6.7% to 54% were reported using Bevacizumab (AvastinR), anti-vascular endothelial growth factor, with chemotherapy. We report the first case of a patient, with a highly vascular breast cancer that recurred locally while on treatment with paclitaxel and trastuzumab combination, but showed complete clinical and pathological regression upon the addition of bevacizumab therapy to the same combination. Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Bevacizumab Breast cancer Trastuzumab Resistance
Case presentation A 54 years old female was diagnosed in October 2002 with a locally advanced left breast cancer and treated with 4 cycles of neoadjuvant chemotherapy consisting of 4 cycles of 5 fluorouracil, Adriamycin and cyclophosphamide then 4 cycles of taxotere (100 mg/m2, a cycle every three weeks), followed by modified radical mastectomy. Histopathologic examination revealed infiltrating ductal carcinoma, T4N2M0, grade III/III. Estrogen and progesterone receptors were negative and HER2/neu was overexpressed þ3/3. She received adjuvant Adriamycin-cyclophosphamide for 4 cycles then Taxotere every 3 weeks for 4 cycles, followed by radiation therapy from April 2002 till November 2002. In September 2003, she developed a limited local recurrence and was treated with surgical excision and weekly paclitaxel and trastuzumab for 24 weeks, after which paclitaxel was stopped and trastuzumab weekly was continued. In March 2004, she developed a left chest wall skin lesion that was treated with carboplatin, paclitaxel and trastuzumab for five months. A repeat skin biopsy on August 2004 showed persistence of metastatic skin lesions and patient was switched to cisplatin, vinorelbine, and trastuzumab for 6 cycles, till December 2004 with partial response. Residual skin lesion was managed by surgical excision with full thickness skin graft. In January 2006, she developed a new right breast mass which turned out to be a new primary
* Corresponding author. Tel.: þ961 3 344277; fax: þ961 3 370814. E-mail addresses: [email protected] (M.H. Farhat), cyberia.net.lb (N.S. El-Saghir), [email protected] (A.I. Shamseddine). 0960-9776/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2008.09.007
elsaghir@
breast cancer for which she received paclitaxel and trastuzumab weekly for 12 weeks with 50% response, followed by modified radical mastectomy in March 2006, radiotherapy and weekly paclitaxel and trastuzumab. Histopathology revealed highly vascularized infiltrating ductal carcinoma (Fig. 1), estrogen and progesterone receptors negative and HER2/neu overexpressed þ3/3, with 19 positive axillary lymph nodes out of 26 (T3N1M0). Twelve weeks after surgery, and while on treatment with paclitaxel and trastuzumab, a local recurrence was noted as a 1.5 by 1.5 cm skin lesion along the mastectomy scar on the right chest wall with no evidence of distant metastasis as confirmed by computed tomography. Skin biopsy showed metastatic breast cancer. In June 2006, bevacizumab 10 mg/kg every two weeks, was added to paclitaxel and trastuzumab. The right chest wall skin lesion gradually decreased in size and completely disappeared after 10 weeks of therapy. A repeat punch biopsy of the original site of recurrence showed no malignant cells (Fig. 2). The patient was maintained on trastuzumab and bevacizumab for a total of one year, last dose in May 2007. The patient is still in remission up to the date of this report. Discussion Neovascular formation is an important biological process under physiologic conditions,1 and a crucial element for the growth,2 invasiveness,3 and metastasis4 of tumors. Because of the central role it plays in tumor growth, angiogenesis represents a therapeutic target for patients with cancer,5 particularly those with chemotherapy resistant tumors.
M.H. Farhat et al. / The Breast 18 (2009) 66–68
Fig. 1. Low power view showing the epidermis and underlying dermal vessels containing tumor (H&E, 40).
Novel biological agents provide the opportunity to improve efficacy of cancer therapy with minimal additional toxicity. Among these agents is bevacizumab (AvastinR), the anti-vascular endothelial growth factor, which has shown a positive additive clinical effect when added to either chemotherapy or trastuzumab in breast cancer with an overall response rates ranging from 6.7% to 54%.6–9 Few preclinical studies suggested that the addition of the antiVEGF, bevacizumab, could overcome trastuzumab’s resistance by the tumor and therefore provide a rationale for combined drugs that target both erb-2 and VEGF.10 However, no clinical trial has yet looked at the effect of the addition of bevacizumab to modify tumor response in breast cancers that have become resistant and progressed while being on chemotherapy and/or trastuzumab. Studies of bevacizumab in combination with chemotherapy have shown positive results.7,9,11 In the E 2100 trial that involved previously untreated metastatic breast cancer patients, the addition of bevacizumab to paclitaxel resulted in doubling of response rate and near doubling in progression free survival, compared to paclitaxel alone.11 However, HER2 positive patients were excluded in this study.
Fig. 2. The punch biopsy taken after treatment: dermis and underlying dermal vessels devoid of tumor (H&E 200).
67
In an analysis of tumors from 611 breast cancer patients, HER2/ neu-overexpressing tumors were found to significantly express more VEGF than HER2/neu-nonoverexpressing tumors.12 HER2/ neu receptors increase VEGF directly by inducing its production,13 and indirectly by enhancing its secretion through heregulin.14 In vitro studies showed that exposure to anti-HER2/neu antibodies or trastuzumab significantly decreases VEGF in cells overexpressing HER2/neu.13,14 This positive association between HER2/neu and VEGF expression supports the use of combination therapies directed against both HER2/neu and VEGF for treatment of breast cancers that overexpress HER2/neu.8 This has been translated clinically when bevacizumab was combined with trastuzumab in a 2-antibody therapeutic strategy for HER2/neu overexpressing breast cancer in a phase II trial. Results were encouraging with 54% of patients showing complete or partial response.15 None of the trials examined the concomitant use of both monoclonal antibodies (bevacizumab and trastuzumab) with chemotherapy in advanced breast cancer. No other clinical cases with a combined therapy of trastuzumab and bevacizumab have been reported in the literature. This response could either be a direct effect of bevacizumab, or a reversal of resistance to chemotherapy and trastuzumab. Synergism is another possibility although the tumor was already resistant to chemotherapy and trastuzumab. In conclusion, we report the first case of a patient, with a highly vascular breast cancer that recurred locally while on treatment with paclitaxel and trastuzumab combination, but showed complete clinical and pathological regression upon the addition of bevacizumab therapy to the same combination. We suggest that the addition of bevacizumab to chemotherapy and trastuzumab deserve to be investigated in clinical trials. Conflict of interest statement None. References 1. Otrock ZK, Makarem JA, Shamseddine AI. Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol Dis 2007;38:258–68. 2. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990;82:4–6. 3. Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 1995;36:127–37. 4. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994;79:185–8. 5. de Castro Junior G, Puglisi F, de Azambuja E, El Saghir NS, Awada A. Angiogenesis and cancer: a cross-talk between basic science and clinical trials (the ‘‘do ut des’’ paradigm). Crit Rev Oncol Hematol 2006;59:40–50. 6. Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 2003;30(5 Suppl. 16):117–24. 7. Wedam SB, Low JA, Yang SX, Chow CK, Choyke P, Danforth D, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 2006;24:769–77. 8. Pegram MD, Reese DM. Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor. Semin Oncol 2002;29(Suppl. 11):29–37. 9. Ramaswamy B, Elias AD, Kelbick NT, Dodley A, Morrow M, Hauger M, et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9. 10. du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, et al. Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts. Clin Cancer Res 2006;12:904–16. 11. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9. 12. Konecny GE, Meng YG, Untch M, Wang HJ, Bauerfeind I, Epstein M, et al. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 2004;10:1706–16. 13. Epstein M, Ayala R, Tchekmedyian N, Borgstrom P, Pegram M, Slamon D. HER2overexpressing human breast cancer xenografts exhibit increased angiogenic
68
M.H. Farhat et al. / The Breast 18 (2009) 66–68
potential mediated by vascular endothelial growth factor (VEGF). Breast Cancer Res Treat 2002;76(Suppl. 1):S143. 14. Yen L, You XL, Al Moustafa AE, Batist G, Hynes NE, Mader S, et al. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 2000;19:3460–9.
15. Pegram M, Chan D, Dichmann RA, Tan-Chiu E, Yeon C, Durna L, et al. Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor (VEGF) using trastuzumab (T) and bevacizumab (B) as first-line treatment of HER2-amplified breast cancer. In: Presented at the 29th annual San Antonio breast cancer symposium, San Antonio, Texas; December 14–17, 2006.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Short Report
Modified resistance to chemotherapy and trastuzumab by bevacizumab in locally recurrent breast cancer Mirna H. Farhat, Nagi S. El-Saghir, Ali I. Shamseddine* American University of Beirut-Medical center, Internal medicine-Division of Hematology-Oncology, P.O. Box: 11-0236/E21-Tumor registry, Riad El – Solh 11070720, Beirut-Lebanon
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 April 2007 Received in revised form 9 September 2008 Accepted 25 September 2008
Antiangiogenic therapy is a valuable new approach in the treatment of breast cancer. Response rates ranging from 6.7% to 54% were reported using Bevacizumab (AvastinR), anti-vascular endothelial growth factor, with chemotherapy. We report the first case of a patient, with a highly vascular breast cancer that recurred locally while on treatment with paclitaxel and trastuzumab combination, but showed complete clinical and pathological regression upon the addition of bevacizumab therapy to the same combination. Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Bevacizumab Breast cancer Trastuzumab Resistance
Case presentation A 54 years old female was diagnosed in October 2002 with a locally advanced left breast cancer and treated with 4 cycles of neoadjuvant chemotherapy consisting of 4 cycles of 5 fluorouracil, Adriamycin and cyclophosphamide then 4 cycles of taxotere (100 mg/m2, a cycle every three weeks), followed by modified radical mastectomy. Histopathologic examination revealed infiltrating ductal carcinoma, T4N2M0, grade III/III. Estrogen and progesterone receptors were negative and HER2/neu was overexpressed þ3/3. She received adjuvant Adriamycin-cyclophosphamide for 4 cycles then Taxotere every 3 weeks for 4 cycles, followed by radiation therapy from April 2002 till November 2002. In September 2003, she developed a limited local recurrence and was treated with surgical excision and weekly paclitaxel and trastuzumab for 24 weeks, after which paclitaxel was stopped and trastuzumab weekly was continued. In March 2004, she developed a left chest wall skin lesion that was treated with carboplatin, paclitaxel and trastuzumab for five months. A repeat skin biopsy on August 2004 showed persistence of metastatic skin lesions and patient was switched to cisplatin, vinorelbine, and trastuzumab for 6 cycles, till December 2004 with partial response. Residual skin lesion was managed by surgical excision with full thickness skin graft. In January 2006, she developed a new right breast mass which turned out to be a new primary
* Corresponding author. Tel.: þ961 3 344277; fax: þ961 3 370814. E-mail addresses: [email protected] (M.H. Farhat), cyberia.net.lb (N.S. El-Saghir), [email protected] (A.I. Shamseddine). 0960-9776/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2008.09.007
elsaghir@
breast cancer for which she received paclitaxel and trastuzumab weekly for 12 weeks with 50% response, followed by modified radical mastectomy in March 2006, radiotherapy and weekly paclitaxel and trastuzumab. Histopathology revealed highly vascularized infiltrating ductal carcinoma (Fig. 1), estrogen and progesterone receptors negative and HER2/neu overexpressed þ3/3, with 19 positive axillary lymph nodes out of 26 (T3N1M0). Twelve weeks after surgery, and while on treatment with paclitaxel and trastuzumab, a local recurrence was noted as a 1.5 by 1.5 cm skin lesion along the mastectomy scar on the right chest wall with no evidence of distant metastasis as confirmed by computed tomography. Skin biopsy showed metastatic breast cancer. In June 2006, bevacizumab 10 mg/kg every two weeks, was added to paclitaxel and trastuzumab. The right chest wall skin lesion gradually decreased in size and completely disappeared after 10 weeks of therapy. A repeat punch biopsy of the original site of recurrence showed no malignant cells (Fig. 2). The patient was maintained on trastuzumab and bevacizumab for a total of one year, last dose in May 2007. The patient is still in remission up to the date of this report. Discussion Neovascular formation is an important biological process under physiologic conditions,1 and a crucial element for the growth,2 invasiveness,3 and metastasis4 of tumors. Because of the central role it plays in tumor growth, angiogenesis represents a therapeutic target for patients with cancer,5 particularly those with chemotherapy resistant tumors.
M.H. Farhat et al. / The Breast 18 (2009) 66–68
Fig. 1. Low power view showing the epidermis and underlying dermal vessels containing tumor (H&E, 40).
Novel biological agents provide the opportunity to improve efficacy of cancer therapy with minimal additional toxicity. Among these agents is bevacizumab (AvastinR), the anti-vascular endothelial growth factor, which has shown a positive additive clinical effect when added to either chemotherapy or trastuzumab in breast cancer with an overall response rates ranging from 6.7% to 54%.6–9 Few preclinical studies suggested that the addition of the antiVEGF, bevacizumab, could overcome trastuzumab’s resistance by the tumor and therefore provide a rationale for combined drugs that target both erb-2 and VEGF.10 However, no clinical trial has yet looked at the effect of the addition of bevacizumab to modify tumor response in breast cancers that have become resistant and progressed while being on chemotherapy and/or trastuzumab. Studies of bevacizumab in combination with chemotherapy have shown positive results.7,9,11 In the E 2100 trial that involved previously untreated metastatic breast cancer patients, the addition of bevacizumab to paclitaxel resulted in doubling of response rate and near doubling in progression free survival, compared to paclitaxel alone.11 However, HER2 positive patients were excluded in this study.
Fig. 2. The punch biopsy taken after treatment: dermis and underlying dermal vessels devoid of tumor (H&E 200).
67
In an analysis of tumors from 611 breast cancer patients, HER2/ neu-overexpressing tumors were found to significantly express more VEGF than HER2/neu-nonoverexpressing tumors.12 HER2/ neu receptors increase VEGF directly by inducing its production,13 and indirectly by enhancing its secretion through heregulin.14 In vitro studies showed that exposure to anti-HER2/neu antibodies or trastuzumab significantly decreases VEGF in cells overexpressing HER2/neu.13,14 This positive association between HER2/neu and VEGF expression supports the use of combination therapies directed against both HER2/neu and VEGF for treatment of breast cancers that overexpress HER2/neu.8 This has been translated clinically when bevacizumab was combined with trastuzumab in a 2-antibody therapeutic strategy for HER2/neu overexpressing breast cancer in a phase II trial. Results were encouraging with 54% of patients showing complete or partial response.15 None of the trials examined the concomitant use of both monoclonal antibodies (bevacizumab and trastuzumab) with chemotherapy in advanced breast cancer. No other clinical cases with a combined therapy of trastuzumab and bevacizumab have been reported in the literature. This response could either be a direct effect of bevacizumab, or a reversal of resistance to chemotherapy and trastuzumab. Synergism is another possibility although the tumor was already resistant to chemotherapy and trastuzumab. In conclusion, we report the first case of a patient, with a highly vascular breast cancer that recurred locally while on treatment with paclitaxel and trastuzumab combination, but showed complete clinical and pathological regression upon the addition of bevacizumab therapy to the same combination. We suggest that the addition of bevacizumab to chemotherapy and trastuzumab deserve to be investigated in clinical trials. Conflict of interest statement None. References 1. Otrock ZK, Makarem JA, Shamseddine AI. Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol Dis 2007;38:258–68. 2. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990;82:4–6. 3. Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 1995;36:127–37. 4. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994;79:185–8. 5. de Castro Junior G, Puglisi F, de Azambuja E, El Saghir NS, Awada A. Angiogenesis and cancer: a cross-talk between basic science and clinical trials (the ‘‘do ut des’’ paradigm). Crit Rev Oncol Hematol 2006;59:40–50. 6. Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 2003;30(5 Suppl. 16):117–24. 7. Wedam SB, Low JA, Yang SX, Chow CK, Choyke P, Danforth D, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 2006;24:769–77. 8. Pegram MD, Reese DM. Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor. Semin Oncol 2002;29(Suppl. 11):29–37. 9. Ramaswamy B, Elias AD, Kelbick NT, Dodley A, Morrow M, Hauger M, et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9. 10. du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, et al. Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts. Clin Cancer Res 2006;12:904–16. 11. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9. 12. Konecny GE, Meng YG, Untch M, Wang HJ, Bauerfeind I, Epstein M, et al. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 2004;10:1706–16. 13. Epstein M, Ayala R, Tchekmedyian N, Borgstrom P, Pegram M, Slamon D. HER2overexpressing human breast cancer xenografts exhibit increased angiogenic
68
M.H. Farhat et al. / The Breast 18 (2009) 66–68
potential mediated by vascular endothelial growth factor (VEGF). Breast Cancer Res Treat 2002;76(Suppl. 1):S143. 14. Yen L, You XL, Al Moustafa AE, Batist G, Hynes NE, Mader S, et al. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 2000;19:3460–9.
15. Pegram M, Chan D, Dichmann RA, Tan-Chiu E, Yeon C, Durna L, et al. Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor (VEGF) using trastuzumab (T) and bevacizumab (B) as first-line treatment of HER2-amplified breast cancer. In: Presented at the 29th annual San Antonio breast cancer symposium, San Antonio, Texas; December 14–17, 2006.