- Email: [email protected]
Case studies of fulvestrant (‘Faslodex’) in postmenopausal women with advanced breast cancer
CANCER TREATMENT REVIEWS (2005) 31, S17–S25
www.elsevierhealth.com/journals/ctrv
Case studies of fulvestrant (‘Faslodex’) in postmenopausal women with advanced breast cancer Paul Abram a,*, Nicolai Maass b, Daniel Rea c, Sergio D. Simon d, Guenther G. Steger e a
Belvoir Park Hospital, Hospital Road, Belfast, Northern Ireland, UK University of Kiel, Kiel, Germany c QEII Hospital, Birmingham, UK d ˜o Paulo, Brazil Hospital Albert Einstein, Sa e University of Vienna, Vienna, Austria b
KEYWORDS
Summary Fulvestrant is a new oestrogen receptor (ER) antagonist that is licensed for the treatment of postmenopausal women with advanced breast cancer progressing following antioestrogen treatment and may also be effective in those progressing after non-steroidal aromatase inhibitors. The use of fulvestrant in a Compassionate Use Programme (CUP) in a ‘real-life’ setting has permitted its activity and tolerability profile in patients with different disease characteristics to be observed. Here, we present five case reports of fulvestrant use in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy. Clinical experience from the CUP supports the published clinical trial data and suggests that fulvestrant is a valuable new treatment for postmenopausal women with advanced breast cancer, including those with visceral metastases and human epidermal growth factor receptor 2-positive disease. c 2005 Elsevier Ltd. All rights reserved.
Advanced breast cancer; Endocrine therapy; Fulvestrant; ‘Faslodex’; Human epidermal growth factor receptor 2; Visceral metastases
Introduction
Breast cancer is the most common cancer in women and there are approximately 210,000 * Corresponding author. Tel.: + 44 2890 699 323; fax: + 44 2890 699 406. E-mail address: [email protected] (P. Abram).
new cases, and approximately 73,000 breast cancer deaths, in the European Union each year (http://www-dep.iarc.fr/eucan/eucan.htm). Although outcomes for patients with breast cancer are improving, they remain poor for those with metastatic disease and treatments for these patients are essentially palliative in nature. Therefore, the primary aims of treatment are a
0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.08.008
S18 sustained duration of response and control of disease-related symptoms using a well-tolerated therapy to help maintain patient quality of life for as long as possible.1 Advanced breast cancer is not often amenable to local management and systemic treatments are usually employed. Endocrine therapy is often the treatment of choice because approximately 75% of breast tumours are hormone receptor (HR)-positive. Moreover, endocrine therapy is not associated with the acute side effects of cytotoxic treatments. There are situations, however, when chemotherapy is utilised early in the treatment sequence, even in patients with HR-positive disease. Such scenarios may include patients who are less likely to respond to endocrine treatment, i.e. those who have experienced prior endocrine therapy failure, younger patients with rapidly progressing, aggressive disease, patients with visceral metastases or patients with human epidermal growth factor receptor 2 (HER2)-positive disease.1–5 Advanced breast cancer is diagnosed most frequently in older women who commonly have comorbid conditions, which can also influence treatment choice and heighten the potential for drug–drug interactions between prescribed treatments. In addition, compliance with cancer treatments may be suboptimal in patients receiving multiple concomitant medications for comorbid conditions, particularly if the treatments rely on regular self-administration. In this situation, a clinician may choose to prescribe a treatment that has to be administered by a healthcare professional.6,7 Patient choice is also becoming increasingly important in treatment decisionmaking, as their beliefs, attitudes and preferences have implications on adherence and are thus important when considering treatment recommendations.8,9 Fulvestrant (‘Faslodex’) is a new endocrine treatment option for postmenopausal women with advanced breast cancer that is administered via a 250 mg monthly intramuscular injection. Fulvestrant is at least as effective and well tolerated as anastrozole in the treatment of postmenopausal women with advanced breast cancer progressing on tamoxifen treatment.10–12 Fulvestrant is also an effective treatment for patients with visceral metastases.13 Fulvestrant has also shown efficacy following the use of aromatase inhibitors14,15 and megestrol acetate16 and thus may lack crossresistance with commonly used endocrine treatments.17,18 Originally licensed in the USA in 2002 for the treatment of postmenopausal women with HR-po-
P. Abram et al. sitive advanced breast cancer with disease progression following antioestrogen therapy, fulvestrant was also approved for similar use in Europe in 2004. Prior to this, it was made available to patients in 28 countries in a Compassionate Use Programme (CUP), with more than 4000 patients receiving fulvestrant treatment as part of the CUP to date. In November 2004, a representative selection of international physicians including patients in the CUP, were invited to share their experiences with fulvestrant. Several interesting case studies were identified during these discussions and are presented below. The following reports illustrate how fulvestrant is proving a useful addition to the armentarium of endocrine treatments for patients with advanced breast cancer.
Case 1 – a sustained response to fulvestrant in a patient who had responded poorly to three prior endocrine treatments In March 2000, patient 1 was diagnosed with pT4bN2M1 grade 2 invasive carcinoma with lung and bone metastases at 75 years of age (Fig. 1). Following modified radical mastectomy with lymph node dissection the tumour was found to be ER-positive, progesterone receptor (PgR)negative and HER2-negative. As anthracyclines were contraindicated (coronary heart disease, chronic atrial fibrillation, cardiac insufficiency) she received docetaxel treatment (seven cycles) and experienced a partial response. This was followed by 4 months of tamoxifen (her first-line palliative endocrine treatment), which resulted in stable disease for a short period prior to progression and treatment discontinuation. Anastrozole treatment was then initiated and resulted in stable disease for 6 months. She received exemestane as her third-line palliative endocrine treatment, but her disease progressed after 3 months. Following this fulvestrant was initiated and her best overall response was a partial response in both her lung and bone lesions. She experienced a sustained duration of response with fulvestrant with a time to progression of 27 months. Following fulvestrant she received three cycles of oral vinorelbine, which failed to stabilise her disease, and so capecitabine was commenced. She received six cycles of capecitabine and her disease stabilised. However, during treatment her cardiac situation deteriorated and she was admitted to the emergency department
Case studies of fulvestrant (‘Faslodex’)
S19
CASE 1 2000
March
Invasive breast carcinoma diagnosed with lung and bone metastases surgery (ER-positive/PgR-negative, HER2-negative) docetaxel (PR)
2001
November
Tamoxifen (SD 4 months)
March
PD, tamoxifen discontinued anastrozole (SD 6 months)
September
PD, anastrozole discontinued exemestane (PD)
2004
December
Fulvestrant initiated (PR in lung + bone lesions 27 months)
March
PD, fulvestrant discontinued vinorelbine (PD)
2005
June
Capecitabine initiated (6 cycles; SD)
January
Congestive heart failure during capecitabine treatment patient died
ER, oestrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; PR, partial response; SD, stable disease
Figure 1 Case 1 – sustained response to fulvestrant in a patient who had responded poorly to three prior endocrine treatments.
for congestive heart failure and died in January 2005. The postmortem determined cardiac decompensation and progressive breast cancer as the reasons for death. It is interesting that this patient appeared to respond better to fulvestrant than to her prior endocrine therapies. It is possible that this is because fulvestrant is administered by a healthcare professional, which may result in improved compliance.
Case 2 – disease control with fulvestrant in a patient with HER2-positive lung metastases from a HER2-negative primary and bone and cerebral metastases Patient 2 presented in October 1993, aged 50 years, with T1N0M0 grade 2 infiltrating ductal carcinoma (Fig. 2). The patient was treated with total
mastectomy and underwent immediate reconstruction. The tumour was found to be ER-positive, PgRpositive and HER2-negative. As adjuvant treatment she received six cycles of cyclophoshamide/methotrexate/5-fluorouracil (CMF), but no adjuvant endocrine therapy was given. In 1998, her disease recurred and she presented with bone and lung metastases. Tamoxifen and pamidronate were prescribed as her first-line endocrine treatment and she experienced stable disease for 18 months. She experienced disease progression in 2000 and a fine-needle biopsy of the lung nodule was performed. This revealed metastatic ER-positive (PgR undetermined) carcinoma with HER2-positive (+++) status. Anastrozole was given as her secondline endocrine treatment, along with trastuzumab together with vinorelbine (for 7 months) and she experienced a partial response, which was sustained for 28 months. In 2003, she developed bone pain and restaging showed progression of the disease in lung and bone as well as the appearance
S20
P. Abram et al. CASE 2 1993
Infiltrating ductal carcinoma diagnosed surgery (ER-positive/PgR-positive, HER2-negative) adjuvant CMF (6 cycles)
1998
Disease recurred, bone and lung metastases diagnosed tamoxifen + pamidronate (SD 18 months)
2000
PD, tamoxifen + pamidronate discontinued lung biopsy (ER-positive, HER2-positive) anastrozole + vinorelbine + trastuzumab (PR 28 months)
2003
PD in lung and bone metastases, cerebral metastases diagnosed radiosurgery + RT (CR in brain) fulvestrant + trastuzumab (SD in bone and lung 13 months)
2005
PD, megestrol acetate initiated (SD)
ER, oestrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; CMF, cyclophosphamide, metrotrexate, 5-fluorouracil; SD, stable disease; PD, disease progression; PR, partial response; CR, complete response; RT, radiotherapy
Figure 2 Case 2 – disease control with fulvestrant in a patient with HER2-positive lung metastases from a HER2negative primary and bone and cerebral metastases.
Figure 3
Magnetic resonance imagery (MRI) scans showing cerebral metastases in the posterior fossa (Case 2).
of cerebral metastases, mostly in the posterior fossa (Fig. 3). She received whole brain radiotherapy and radiosurgery and was switched to fulvestrant; trastuzumab treatment was also continued. She experienced a complete response in the brain following radiotherapy and had stable disease in bone and lung sites. She gained clinical benefit from fulvestrant/ trastuzumab for 13 months and was subsequently prescribed megestrol acetate to which she experienced stable disease.
Case 3 – sustained response to fulvestrant in a patient having previously undergone eight resections and two prior endocrine therapies for recurrent breast cancer Patient 3 was a fit 44-year-old woman who presented in 1989 with a breast lump. She was found to have a well-differentiated carcinoma and her
Case studies of fulvestrant (‘Faslodex’) primary treatment was a left wide local excision (WLE) with radiotherapy to the breast and adjuvant tamoxifen (Fig. 4). In 1993, she experienced an ‘in-breast’ local recurrence; tamoxifen was discontinued and she underwent mastectomy (resection 1) of her left breast. In 1996, she experienced a left axillary node recurrence (resection 2), was given CMF chemotherapy and tamoxifen treatment was restarted. In 1997, she experienced a further left axillary recurrence (resection 3); radiotherapy was administered to the left axillary region/supraclavicular fossa and tamoxifen was discontinued. She had two further left axillary recurrences in the next 18 months (resections 4 and 5). Histological assessment of a further left
S21 axillary recurrence (resection 6) in November 1999 revealed an ER-positive, PgR-positive, HER2-negative tumour. At this stage anastrozole treatment was initiated. Following resection of a further left axillary recurrence (resection 7) in March 2001, the patient received exemestane. When a further left axillary recurrence occurred in February 2003 (resection 8), this patient was administered fulvestrant as her third-line endocrine treatment. As of March 2005, the patient was well, had experienced no adverse events, had been in remission for 24 months and was still receiving fulvestrant treatment. In this case fulvestrant was administered by a practice nurse at a local general practice clinic.
CASE 3 1989
Breast cancer diagnosed WLE + adjuvant RT; tamoxifen
1993
Local recurrence mastectomy, tamoxifen discontinued
1996
Axillary node recurrence surgery; CMF; tamoxifen restarted
1997
Axillary node recurrence surgery; RT; tamoxifen discontinued
1998
Axillary node recurrence surgery
1999
March
Axillary node recurrence surgery
November
Axillary node recurrence surgery (ER-positive/PgR-positive, HER2-negative) anastrozole
2001
March
Axillary node recurrence surgery; exemestane
2003
February
Axillary node recurrence surgery; fulvestrant
2005
March
Patient well in remission (24 months), no AEs, still receiving fulvestrant
WLE, wide lump excision; RT, radiotherapy; CMF, cyclophosphamide, metrotrexate, 5-fluourouracil; ER, oestrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor 2; AEs, adverse events
Figure 4 Case 3 – sustained response to fulvestrant in a patient having previously undergone eight resections and three prior endocrine therapies for recurrent breast cancer.
S22
P. Abram et al.
Case 4 – efficacy of fulvestrant in a patient with HER2-positive disease and multiple sites of metastases Patient 4, a 52-year old woman, was diagnosed in November 2000 with invasive ductal T3pN1M0 carcinoma that was positive for both ER and PgR, and also overexpressed HER2 (+++) (Fig. 5). She underwent a mastectomy with axillary node dissection and received adjuvant treatment consisting of four cycles of epirubicin/cyclophosphamide (EC) and 5 months of tamoxifen. In May 2001, her disease had recurred and she was diagnosed with bone, lung and pleura metastases. She received paclitaxel/trastuzumab for 6 months followed by trastuzumab alone for a further year. In December 2002, she underwent surgery for a chest wall recurrence (local excision) and received adjuvant radiotherapy. In May 2003, her bone metastases progressed and anastrozole treatment was initiated the following month. In January 2004, she experienced progression in bone, lung and pleura metastatic sites and second-line fulvestrant treatment commenced. This patient experienced a partial response of 6 months duration with fulvestrant
and also had a mild reaction at the injection site. In September 2004, her bone disease progressed and she developed liver metastases, therefore fulvestrant was discontinued and gemcitabine initiated. Disease stabilised for a short time on gemcitabine, however, in December 2004, she was admitted with progressive disease (ascites, progression of liver metastases and para-aortal lymphoma) and no further therapy was possible other than analgesic medication. This patient died later that month.
Case 5 – efficacy of fulvestrant in a patient with node, bone and lung metastases and Dukes’ stage B colon cancer Patient 5 was 61 years of age when she was diagnosed with a tumour in the left breast (April 1989) [Fig. 6]. She received a partial mastectomy and axillary node sampling and was found to have a T2N1M0 grade 2 tumour. Approximately 4 years after completing a 5-year course of adjuvant tamoxifen, the patient experienced a relapse in the left axilla. In November 1998, the tumour in
CASE 4 2000
November
Invasive ductal carcinoma diagnosed mastectomy + axillary dissection (ER-positive, PgR-positive, HER2-positive) adjuvant EC (4 cycles); tamoxifen (5 months)
2001
May
PD; bone, lung and pleura metastases diagnosed paclitaxel/trastuzumab (6 months); trastuzumab (12 months)
2002
December
Surgery for chest wall recurrence adjuvant RT
2003
May/June
PD in bone metastases anastrozole (SD)
2004
January
PD in bone, lung and pleura metastases fulvestrant (PR 6 months)
2004
September
PD in bone metastases, liver metastases diagnosed gemcitabine
December
PD in liver metastases, ascites + para-aortal lymphoma diagnosed patient died
ER, oestrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; EC, epirubicin, cyclophosphamide; PD, disease progression; RT, radiotherapy; PR, partial response
Figure 5
Case 4 – efficacy of fulvestrant in a patient with HER2-positive disease and multiple sites of metastases.
Case studies of fulvestrant (‘Faslodex’)
S23
CASE 5 1989
April
Breast cancer diagnosed partial mastectomy and axillar y node dissection (T 2N1M0, grade 2) adjuvant tamoxifen (5 years)
1998
November
Relapse in left axilla surgery, sub-totally excised (ER-positive) anastrozole initiated
1999
January
PD in left axilla
2000
November
Duke's Stage B colon cancer diagnosed right hemicolectomy
2002
September
PD in left axilla
2003
January
Anastrozole discontinued
February
Fulvestrant initiated
June
SD in left axilla, possible lung and bone metastases
2004
October
SD in left axilla and lungs
2005
February
SD in bone (treatment ongoing; SD 25+ months)
ER, oestrogen receptor; PD, disease progression; SD, stable disease
Figure 6 cancer.
Case 5 – efficacy of fulvestrant in a patient with node, bone and lung metastases and Dukes’ stage B colon
the left axilla was sub-totally excised and found to be ER-positive and anastrozole was administered as first-line endocrine treatment for advanced disease. After 3 months, she experienced disease progression and a 2 cm mass was present in the left axilla. Two years later she was diagnosed with a new primary tumour – a moderately differentiated adenocarcinoma of the ascending colon (Dukes’ stage B colon cancer) and she underwent a right hemicolectomy. In September 2002, she experienced disease progression once again in the left axilla and, anastrozole treatment was discontinued in January 2003. In February 2003, fulvestrant treatment was initiated as her second-line endocrine treatment. After 4 months of treatment, a computed tomography (CT) scan showed stable disease
in the left axilla, but the presence of lung and bone metastases was suggested. Her next two scans (August and October 2003) showed stable disease in the lungs/left axilla (Fig. 7) and the patient was well enough to take a family holiday. At the next two follow-up visits (April and May 2004), the left axillary mass was unchanged; the patient was doing well and had no respiratory symptoms. At a followup visit in October 2004, the patient was doing well, with clinically stable disease. At this visit, repeat CT scans were performed and the disease was confirmed to be stable in the lungs and left axilla. A repeat isotope bone scan was performed early in February 2005, which confirmed her bone metastases were also stable. At latest follow-up (14 February 2005), the patient was still doing well and at
S24
P. Abram et al.
Figure 7 Prolonged duration of stable disease with fulvestrant. (a) Bone scan images, (b) Computed tomography (CT) scans showing metastases in the left axilla (Case 5).
this point had been experiencing stable disease with fulvestrant for 25 months.
Summary These cases add to the growing clinical experience of fulvestrant in a ‘real-life’ setting and provide further insight into the use of this agent in patients with different disease characteristics. Fulvestrant has clear efficacy in patients with tamoxifen-resistant disease12 and there is evidence that it may also be effective in patients progressing after non-steroidal aromatase inhibitor treatment.14,15 Data from the CUP support the lack of cross-resistance between fulvestrant and other commonly used endocrine treatments. As observed in clinical trials,13 we have seen sustained responses in patients with varying disease characteristics including those with visceral, central nervous system or multiple sites of metastases. This is also in accordance with previous observations that some patients experience prolonged durations of response with fulvestrant treatment.19 Fulvestrant also showed evidence of activity as
monotherapy in those with HER2-positive disease – a patient population that is often resistant to endocrine therapy20,21 and thus may be selected for aggressive chemotherapy or trastuzumab treatment.22 Fulvestrant may therefore offer a well tolerated and effective alternative for some patients with poor prognosis disease. Our observations highlight the value of this agent in the sequential treatment of postmenopausal women with advanced breast cancer. Data from the CUP and the individual case studies support the use of fulvestrant as second- to sixth-line endocrine treatment in patients with a wide range of metastases and tumours with different biological properties. The good responses seen from its use late in the treatment sequence, along with its very good tolerability profile support the use of fulvestrant earlier on in the sequence. Fulvestrant is currently licensed for use in patients recurring or progressing on prior antioestrogen therapy and the use of it in such patients would allow more women to experience the potential benefits of this agent. Future and ongoing clinical trials are discussed in the next paper in this supplement23 and will more clearly define the role of fulvestrant in the management of advanced breast cancer.
Case studies of fulvestrant (‘Faslodex’)
References 1. Chung CT, Carlson RW. Goals and objectives in the management of metastatic breast cancer. Oncologist 2003;8:514–20. 2. Harmsen Jr HJ, Porsius AJ. Endocrine therapy of breast cancer. Eur J Cancer Clin Oncol 1988;24:1099–116. 3. Robertson JF, Dixon AR, Nicholson RI, Ellis IO, Elston CW, Blamey RW. Confirmation of a prognostic index for patients with metastatic breast cancer treated by endocrine therapy. Breast Cancer Res Treat 1992;22:221–7. 4. Curigliano G, Rigo R, Colleoni M, et al. Adjuvant therapy for very young women with breast cancer: response according to biologic and endocrine features. Clin Breast Cancer 2004;5:125–30. 5. Menard S, Casalini P, Campiglio M, Pupa SM, Tagliabue E. Role of HER2/neu in tumor progression and therapy. Cell Mol Life Sci 2004;61:2965–78. 6. Robertson JFR. Incidence of polypharmacy in patients with breast cancer. The Breast 2005;14:S39. 7. Robertson JFR. Incidence of polypharmacy in patients with breast cancer. In: Poster presentation at the Ninth International Conference on Primary Therapy of Breast Cancer, 26– 29 January 2005, St. Gallen, Switzerland (poster 83). 8. Fallowfield L, Atkins L, Morris R, et al. Routes of administration in breast cancer: preliminary findings from a patient survey. The Breast 2005;14(Suppl. 1):S51.. (abstr P126). 9. Fallowfield L, Atkins L, Morris R, et al. Routes of administration in breast cancer: preliminary findings from a patient survey. In: Poster presentation at the Ninth International Conference on Primary Therapy of Breast Cancer, 26–29 January 2005, St Gallen, Switzerland (poster 126). 10. Howell A, Robertson JFR, Quaresma AJ, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002;20:3396–403. 11. Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 2002;20:3386–95. 12. Robertson JF, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women – a prospective combined analysis of two multicenter trials. Cancer 2003;98:229–38.
S25 13. Mauriac L, Pippen JE, Quaresma AJ, Gertler SZ, Osborne CK. Fulvestrant (Faslodex) versus anastrozole for the secondline treatment of advanced breast cancer in subgroups of postmenopausal women with visceral and non-visceral metastases: combined results from two multicentre trials. Eur J Cancer 2003;39:1228–33. 14. Ingle JN, Rowland KM, Suman VJ, et al. Evaluation of fulvestrant in women with advanced breast cancer and progression on prior aromatase inhibitor therapy: a phase II trial of the North Central Cancer Treatment Group. Breast Cancer Res Treat 2004;88(Suppl. 1):S38.. (abstr 409). 15. Perey L, Paridaens R, Nole ´ F, et al. Fulvestrant (Faslodexä) as hormonal treatment in postmenopausal patients with advanced breast cancer (ABC) progressing after treatment with tamoxifen and aromatase inhibitors: update of a phase II SAKK trial. Breast Cancer Res Treat 2004;88 (Suppl. 1): S236.. (abstr 6048). 16. Steger G, Bartsch R, Wenzel C, et al. Fulvestrant (FaslodexÒ) in metastatic breast cancer. Breast Cancer Res Treat 2003;82(Suppl. 1):S104.. (abstr 437). 17. Franco S, Perez A, Tan-Chiu E, Frankel C, Vogel CL. Response to fulvestrant in heavily pretreated postmenopausal women: a single-center experience. Breast Cancer Res Treat 2004;88:103–8. 18. Petruzelka L, Zimovjanova M, Konopasek B, Mares P, Dlouha Z. Fulvestrant in postmenopausal women with metastatic breast cancer progressing on prior endocrine therapy – updated results from an expanded access programme. Ann Oncol 2004;15(Suppl. 3):iii36.. (abstr 136P). 19. Jones SE, Pippen J, Webster A. A retrospective analysis of the proportion of patients responding for >1, 1.5 and 2 years in two phase III studies of fulvestrant versus anastrozole. Breast Cancer Res Treat 2004;88(Suppl. 1): S236.. (abstr 6047). 20. Houston SJ, Plunkett TA, Barnes DM, Smith P, Rubens RD, Miles DW. Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 1999;79:1220–6. 21. Dowsett M, Harper-Wynne C, Boeddinghaus I, et al. HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptorpositive primary breast cancer. Cancer Res 2001;61: 8452–8. 22. Menard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene 2003;22:6570–8. 23. Howell A. The future of fulvestrant (‘Faslodex’). Cancer Treatment Rev 2005;31(Suppl. 2):S26–33.
www.elsevierhealth.com/journals/ctrv
Case studies of fulvestrant (‘Faslodex’) in postmenopausal women with advanced breast cancer Paul Abram a,*, Nicolai Maass b, Daniel Rea c, Sergio D. Simon d, Guenther G. Steger e a
Belvoir Park Hospital, Hospital Road, Belfast, Northern Ireland, UK University of Kiel, Kiel, Germany c QEII Hospital, Birmingham, UK d ˜o Paulo, Brazil Hospital Albert Einstein, Sa e University of Vienna, Vienna, Austria b
KEYWORDS
Summary Fulvestrant is a new oestrogen receptor (ER) antagonist that is licensed for the treatment of postmenopausal women with advanced breast cancer progressing following antioestrogen treatment and may also be effective in those progressing after non-steroidal aromatase inhibitors. The use of fulvestrant in a Compassionate Use Programme (CUP) in a ‘real-life’ setting has permitted its activity and tolerability profile in patients with different disease characteristics to be observed. Here, we present five case reports of fulvestrant use in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy. Clinical experience from the CUP supports the published clinical trial data and suggests that fulvestrant is a valuable new treatment for postmenopausal women with advanced breast cancer, including those with visceral metastases and human epidermal growth factor receptor 2-positive disease. c 2005 Elsevier Ltd. All rights reserved.
Advanced breast cancer; Endocrine therapy; Fulvestrant; ‘Faslodex’; Human epidermal growth factor receptor 2; Visceral metastases
Introduction
Breast cancer is the most common cancer in women and there are approximately 210,000 * Corresponding author. Tel.: + 44 2890 699 323; fax: + 44 2890 699 406. E-mail address: [email protected] (P. Abram).
new cases, and approximately 73,000 breast cancer deaths, in the European Union each year (http://www-dep.iarc.fr/eucan/eucan.htm). Although outcomes for patients with breast cancer are improving, they remain poor for those with metastatic disease and treatments for these patients are essentially palliative in nature. Therefore, the primary aims of treatment are a
0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.08.008
S18 sustained duration of response and control of disease-related symptoms using a well-tolerated therapy to help maintain patient quality of life for as long as possible.1 Advanced breast cancer is not often amenable to local management and systemic treatments are usually employed. Endocrine therapy is often the treatment of choice because approximately 75% of breast tumours are hormone receptor (HR)-positive. Moreover, endocrine therapy is not associated with the acute side effects of cytotoxic treatments. There are situations, however, when chemotherapy is utilised early in the treatment sequence, even in patients with HR-positive disease. Such scenarios may include patients who are less likely to respond to endocrine treatment, i.e. those who have experienced prior endocrine therapy failure, younger patients with rapidly progressing, aggressive disease, patients with visceral metastases or patients with human epidermal growth factor receptor 2 (HER2)-positive disease.1–5 Advanced breast cancer is diagnosed most frequently in older women who commonly have comorbid conditions, which can also influence treatment choice and heighten the potential for drug–drug interactions between prescribed treatments. In addition, compliance with cancer treatments may be suboptimal in patients receiving multiple concomitant medications for comorbid conditions, particularly if the treatments rely on regular self-administration. In this situation, a clinician may choose to prescribe a treatment that has to be administered by a healthcare professional.6,7 Patient choice is also becoming increasingly important in treatment decisionmaking, as their beliefs, attitudes and preferences have implications on adherence and are thus important when considering treatment recommendations.8,9 Fulvestrant (‘Faslodex’) is a new endocrine treatment option for postmenopausal women with advanced breast cancer that is administered via a 250 mg monthly intramuscular injection. Fulvestrant is at least as effective and well tolerated as anastrozole in the treatment of postmenopausal women with advanced breast cancer progressing on tamoxifen treatment.10–12 Fulvestrant is also an effective treatment for patients with visceral metastases.13 Fulvestrant has also shown efficacy following the use of aromatase inhibitors14,15 and megestrol acetate16 and thus may lack crossresistance with commonly used endocrine treatments.17,18 Originally licensed in the USA in 2002 for the treatment of postmenopausal women with HR-po-
P. Abram et al. sitive advanced breast cancer with disease progression following antioestrogen therapy, fulvestrant was also approved for similar use in Europe in 2004. Prior to this, it was made available to patients in 28 countries in a Compassionate Use Programme (CUP), with more than 4000 patients receiving fulvestrant treatment as part of the CUP to date. In November 2004, a representative selection of international physicians including patients in the CUP, were invited to share their experiences with fulvestrant. Several interesting case studies were identified during these discussions and are presented below. The following reports illustrate how fulvestrant is proving a useful addition to the armentarium of endocrine treatments for patients with advanced breast cancer.
Case 1 – a sustained response to fulvestrant in a patient who had responded poorly to three prior endocrine treatments In March 2000, patient 1 was diagnosed with pT4bN2M1 grade 2 invasive carcinoma with lung and bone metastases at 75 years of age (Fig. 1). Following modified radical mastectomy with lymph node dissection the tumour was found to be ER-positive, progesterone receptor (PgR)negative and HER2-negative. As anthracyclines were contraindicated (coronary heart disease, chronic atrial fibrillation, cardiac insufficiency) she received docetaxel treatment (seven cycles) and experienced a partial response. This was followed by 4 months of tamoxifen (her first-line palliative endocrine treatment), which resulted in stable disease for a short period prior to progression and treatment discontinuation. Anastrozole treatment was then initiated and resulted in stable disease for 6 months. She received exemestane as her third-line palliative endocrine treatment, but her disease progressed after 3 months. Following this fulvestrant was initiated and her best overall response was a partial response in both her lung and bone lesions. She experienced a sustained duration of response with fulvestrant with a time to progression of 27 months. Following fulvestrant she received three cycles of oral vinorelbine, which failed to stabilise her disease, and so capecitabine was commenced. She received six cycles of capecitabine and her disease stabilised. However, during treatment her cardiac situation deteriorated and she was admitted to the emergency department
Case studies of fulvestrant (‘Faslodex’)
S19
CASE 1 2000
March
Invasive breast carcinoma diagnosed with lung and bone metastases surgery (ER-positive/PgR-negative, HER2-negative) docetaxel (PR)
2001
November
Tamoxifen (SD 4 months)
March
PD, tamoxifen discontinued anastrozole (SD 6 months)
September
PD, anastrozole discontinued exemestane (PD)
2004
December
Fulvestrant initiated (PR in lung + bone lesions 27 months)
March
PD, fulvestrant discontinued vinorelbine (PD)
2005
June
Capecitabine initiated (6 cycles; SD)
January
Congestive heart failure during capecitabine treatment patient died
ER, oestrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; PR, partial response; SD, stable disease
Figure 1 Case 1 – sustained response to fulvestrant in a patient who had responded poorly to three prior endocrine treatments.
for congestive heart failure and died in January 2005. The postmortem determined cardiac decompensation and progressive breast cancer as the reasons for death. It is interesting that this patient appeared to respond better to fulvestrant than to her prior endocrine therapies. It is possible that this is because fulvestrant is administered by a healthcare professional, which may result in improved compliance.
Case 2 – disease control with fulvestrant in a patient with HER2-positive lung metastases from a HER2-negative primary and bone and cerebral metastases Patient 2 presented in October 1993, aged 50 years, with T1N0M0 grade 2 infiltrating ductal carcinoma (Fig. 2). The patient was treated with total
mastectomy and underwent immediate reconstruction. The tumour was found to be ER-positive, PgRpositive and HER2-negative. As adjuvant treatment she received six cycles of cyclophoshamide/methotrexate/5-fluorouracil (CMF), but no adjuvant endocrine therapy was given. In 1998, her disease recurred and she presented with bone and lung metastases. Tamoxifen and pamidronate were prescribed as her first-line endocrine treatment and she experienced stable disease for 18 months. She experienced disease progression in 2000 and a fine-needle biopsy of the lung nodule was performed. This revealed metastatic ER-positive (PgR undetermined) carcinoma with HER2-positive (+++) status. Anastrozole was given as her secondline endocrine treatment, along with trastuzumab together with vinorelbine (for 7 months) and she experienced a partial response, which was sustained for 28 months. In 2003, she developed bone pain and restaging showed progression of the disease in lung and bone as well as the appearance
S20
P. Abram et al. CASE 2 1993
Infiltrating ductal carcinoma diagnosed surgery (ER-positive/PgR-positive, HER2-negative) adjuvant CMF (6 cycles)
1998
Disease recurred, bone and lung metastases diagnosed tamoxifen + pamidronate (SD 18 months)
2000
PD, tamoxifen + pamidronate discontinued lung biopsy (ER-positive, HER2-positive) anastrozole + vinorelbine + trastuzumab (PR 28 months)
2003
PD in lung and bone metastases, cerebral metastases diagnosed radiosurgery + RT (CR in brain) fulvestrant + trastuzumab (SD in bone and lung 13 months)
2005
PD, megestrol acetate initiated (SD)
ER, oestrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; CMF, cyclophosphamide, metrotrexate, 5-fluorouracil; SD, stable disease; PD, disease progression; PR, partial response; CR, complete response; RT, radiotherapy
Figure 2 Case 2 – disease control with fulvestrant in a patient with HER2-positive lung metastases from a HER2negative primary and bone and cerebral metastases.
Figure 3
Magnetic resonance imagery (MRI) scans showing cerebral metastases in the posterior fossa (Case 2).
of cerebral metastases, mostly in the posterior fossa (Fig. 3). She received whole brain radiotherapy and radiosurgery and was switched to fulvestrant; trastuzumab treatment was also continued. She experienced a complete response in the brain following radiotherapy and had stable disease in bone and lung sites. She gained clinical benefit from fulvestrant/ trastuzumab for 13 months and was subsequently prescribed megestrol acetate to which she experienced stable disease.
Case 3 – sustained response to fulvestrant in a patient having previously undergone eight resections and two prior endocrine therapies for recurrent breast cancer Patient 3 was a fit 44-year-old woman who presented in 1989 with a breast lump. She was found to have a well-differentiated carcinoma and her
Case studies of fulvestrant (‘Faslodex’) primary treatment was a left wide local excision (WLE) with radiotherapy to the breast and adjuvant tamoxifen (Fig. 4). In 1993, she experienced an ‘in-breast’ local recurrence; tamoxifen was discontinued and she underwent mastectomy (resection 1) of her left breast. In 1996, she experienced a left axillary node recurrence (resection 2), was given CMF chemotherapy and tamoxifen treatment was restarted. In 1997, she experienced a further left axillary recurrence (resection 3); radiotherapy was administered to the left axillary region/supraclavicular fossa and tamoxifen was discontinued. She had two further left axillary recurrences in the next 18 months (resections 4 and 5). Histological assessment of a further left
S21 axillary recurrence (resection 6) in November 1999 revealed an ER-positive, PgR-positive, HER2-negative tumour. At this stage anastrozole treatment was initiated. Following resection of a further left axillary recurrence (resection 7) in March 2001, the patient received exemestane. When a further left axillary recurrence occurred in February 2003 (resection 8), this patient was administered fulvestrant as her third-line endocrine treatment. As of March 2005, the patient was well, had experienced no adverse events, had been in remission for 24 months and was still receiving fulvestrant treatment. In this case fulvestrant was administered by a practice nurse at a local general practice clinic.
CASE 3 1989
Breast cancer diagnosed WLE + adjuvant RT; tamoxifen
1993
Local recurrence mastectomy, tamoxifen discontinued
1996
Axillary node recurrence surgery; CMF; tamoxifen restarted
1997
Axillary node recurrence surgery; RT; tamoxifen discontinued
1998
Axillary node recurrence surgery
1999
March
Axillary node recurrence surgery
November
Axillary node recurrence surgery (ER-positive/PgR-positive, HER2-negative) anastrozole
2001
March
Axillary node recurrence surgery; exemestane
2003
February
Axillary node recurrence surgery; fulvestrant
2005
March
Patient well in remission (24 months), no AEs, still receiving fulvestrant
WLE, wide lump excision; RT, radiotherapy; CMF, cyclophosphamide, metrotrexate, 5-fluourouracil; ER, oestrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor 2; AEs, adverse events
Figure 4 Case 3 – sustained response to fulvestrant in a patient having previously undergone eight resections and three prior endocrine therapies for recurrent breast cancer.
S22
P. Abram et al.
Case 4 – efficacy of fulvestrant in a patient with HER2-positive disease and multiple sites of metastases Patient 4, a 52-year old woman, was diagnosed in November 2000 with invasive ductal T3pN1M0 carcinoma that was positive for both ER and PgR, and also overexpressed HER2 (+++) (Fig. 5). She underwent a mastectomy with axillary node dissection and received adjuvant treatment consisting of four cycles of epirubicin/cyclophosphamide (EC) and 5 months of tamoxifen. In May 2001, her disease had recurred and she was diagnosed with bone, lung and pleura metastases. She received paclitaxel/trastuzumab for 6 months followed by trastuzumab alone for a further year. In December 2002, she underwent surgery for a chest wall recurrence (local excision) and received adjuvant radiotherapy. In May 2003, her bone metastases progressed and anastrozole treatment was initiated the following month. In January 2004, she experienced progression in bone, lung and pleura metastatic sites and second-line fulvestrant treatment commenced. This patient experienced a partial response of 6 months duration with fulvestrant
and also had a mild reaction at the injection site. In September 2004, her bone disease progressed and she developed liver metastases, therefore fulvestrant was discontinued and gemcitabine initiated. Disease stabilised for a short time on gemcitabine, however, in December 2004, she was admitted with progressive disease (ascites, progression of liver metastases and para-aortal lymphoma) and no further therapy was possible other than analgesic medication. This patient died later that month.
Case 5 – efficacy of fulvestrant in a patient with node, bone and lung metastases and Dukes’ stage B colon cancer Patient 5 was 61 years of age when she was diagnosed with a tumour in the left breast (April 1989) [Fig. 6]. She received a partial mastectomy and axillary node sampling and was found to have a T2N1M0 grade 2 tumour. Approximately 4 years after completing a 5-year course of adjuvant tamoxifen, the patient experienced a relapse in the left axilla. In November 1998, the tumour in
CASE 4 2000
November
Invasive ductal carcinoma diagnosed mastectomy + axillary dissection (ER-positive, PgR-positive, HER2-positive) adjuvant EC (4 cycles); tamoxifen (5 months)
2001
May
PD; bone, lung and pleura metastases diagnosed paclitaxel/trastuzumab (6 months); trastuzumab (12 months)
2002
December
Surgery for chest wall recurrence adjuvant RT
2003
May/June
PD in bone metastases anastrozole (SD)
2004
January
PD in bone, lung and pleura metastases fulvestrant (PR 6 months)
2004
September
PD in bone metastases, liver metastases diagnosed gemcitabine
December
PD in liver metastases, ascites + para-aortal lymphoma diagnosed patient died
ER, oestrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; EC, epirubicin, cyclophosphamide; PD, disease progression; RT, radiotherapy; PR, partial response
Figure 5
Case 4 – efficacy of fulvestrant in a patient with HER2-positive disease and multiple sites of metastases.
Case studies of fulvestrant (‘Faslodex’)
S23
CASE 5 1989
April
Breast cancer diagnosed partial mastectomy and axillar y node dissection (T 2N1M0, grade 2) adjuvant tamoxifen (5 years)
1998
November
Relapse in left axilla surgery, sub-totally excised (ER-positive) anastrozole initiated
1999
January
PD in left axilla
2000
November
Duke's Stage B colon cancer diagnosed right hemicolectomy
2002
September
PD in left axilla
2003
January
Anastrozole discontinued
February
Fulvestrant initiated
June
SD in left axilla, possible lung and bone metastases
2004
October
SD in left axilla and lungs
2005
February
SD in bone (treatment ongoing; SD 25+ months)
ER, oestrogen receptor; PD, disease progression; SD, stable disease
Figure 6 cancer.
Case 5 – efficacy of fulvestrant in a patient with node, bone and lung metastases and Dukes’ stage B colon
the left axilla was sub-totally excised and found to be ER-positive and anastrozole was administered as first-line endocrine treatment for advanced disease. After 3 months, she experienced disease progression and a 2 cm mass was present in the left axilla. Two years later she was diagnosed with a new primary tumour – a moderately differentiated adenocarcinoma of the ascending colon (Dukes’ stage B colon cancer) and she underwent a right hemicolectomy. In September 2002, she experienced disease progression once again in the left axilla and, anastrozole treatment was discontinued in January 2003. In February 2003, fulvestrant treatment was initiated as her second-line endocrine treatment. After 4 months of treatment, a computed tomography (CT) scan showed stable disease
in the left axilla, but the presence of lung and bone metastases was suggested. Her next two scans (August and October 2003) showed stable disease in the lungs/left axilla (Fig. 7) and the patient was well enough to take a family holiday. At the next two follow-up visits (April and May 2004), the left axillary mass was unchanged; the patient was doing well and had no respiratory symptoms. At a followup visit in October 2004, the patient was doing well, with clinically stable disease. At this visit, repeat CT scans were performed and the disease was confirmed to be stable in the lungs and left axilla. A repeat isotope bone scan was performed early in February 2005, which confirmed her bone metastases were also stable. At latest follow-up (14 February 2005), the patient was still doing well and at
S24
P. Abram et al.
Figure 7 Prolonged duration of stable disease with fulvestrant. (a) Bone scan images, (b) Computed tomography (CT) scans showing metastases in the left axilla (Case 5).
this point had been experiencing stable disease with fulvestrant for 25 months.
Summary These cases add to the growing clinical experience of fulvestrant in a ‘real-life’ setting and provide further insight into the use of this agent in patients with different disease characteristics. Fulvestrant has clear efficacy in patients with tamoxifen-resistant disease12 and there is evidence that it may also be effective in patients progressing after non-steroidal aromatase inhibitor treatment.14,15 Data from the CUP support the lack of cross-resistance between fulvestrant and other commonly used endocrine treatments. As observed in clinical trials,13 we have seen sustained responses in patients with varying disease characteristics including those with visceral, central nervous system or multiple sites of metastases. This is also in accordance with previous observations that some patients experience prolonged durations of response with fulvestrant treatment.19 Fulvestrant also showed evidence of activity as
monotherapy in those with HER2-positive disease – a patient population that is often resistant to endocrine therapy20,21 and thus may be selected for aggressive chemotherapy or trastuzumab treatment.22 Fulvestrant may therefore offer a well tolerated and effective alternative for some patients with poor prognosis disease. Our observations highlight the value of this agent in the sequential treatment of postmenopausal women with advanced breast cancer. Data from the CUP and the individual case studies support the use of fulvestrant as second- to sixth-line endocrine treatment in patients with a wide range of metastases and tumours with different biological properties. The good responses seen from its use late in the treatment sequence, along with its very good tolerability profile support the use of fulvestrant earlier on in the sequence. Fulvestrant is currently licensed for use in patients recurring or progressing on prior antioestrogen therapy and the use of it in such patients would allow more women to experience the potential benefits of this agent. Future and ongoing clinical trials are discussed in the next paper in this supplement23 and will more clearly define the role of fulvestrant in the management of advanced breast cancer.
Case studies of fulvestrant (‘Faslodex’)
References 1. Chung CT, Carlson RW. Goals and objectives in the management of metastatic breast cancer. Oncologist 2003;8:514–20. 2. Harmsen Jr HJ, Porsius AJ. Endocrine therapy of breast cancer. Eur J Cancer Clin Oncol 1988;24:1099–116. 3. Robertson JF, Dixon AR, Nicholson RI, Ellis IO, Elston CW, Blamey RW. Confirmation of a prognostic index for patients with metastatic breast cancer treated by endocrine therapy. Breast Cancer Res Treat 1992;22:221–7. 4. Curigliano G, Rigo R, Colleoni M, et al. Adjuvant therapy for very young women with breast cancer: response according to biologic and endocrine features. Clin Breast Cancer 2004;5:125–30. 5. Menard S, Casalini P, Campiglio M, Pupa SM, Tagliabue E. Role of HER2/neu in tumor progression and therapy. Cell Mol Life Sci 2004;61:2965–78. 6. Robertson JFR. Incidence of polypharmacy in patients with breast cancer. The Breast 2005;14:S39. 7. Robertson JFR. Incidence of polypharmacy in patients with breast cancer. In: Poster presentation at the Ninth International Conference on Primary Therapy of Breast Cancer, 26– 29 January 2005, St. Gallen, Switzerland (poster 83). 8. Fallowfield L, Atkins L, Morris R, et al. Routes of administration in breast cancer: preliminary findings from a patient survey. The Breast 2005;14(Suppl. 1):S51.. (abstr P126). 9. Fallowfield L, Atkins L, Morris R, et al. Routes of administration in breast cancer: preliminary findings from a patient survey. In: Poster presentation at the Ninth International Conference on Primary Therapy of Breast Cancer, 26–29 January 2005, St Gallen, Switzerland (poster 126). 10. Howell A, Robertson JFR, Quaresma AJ, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002;20:3396–403. 11. Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 2002;20:3386–95. 12. Robertson JF, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women – a prospective combined analysis of two multicenter trials. Cancer 2003;98:229–38.
S25 13. Mauriac L, Pippen JE, Quaresma AJ, Gertler SZ, Osborne CK. Fulvestrant (Faslodex) versus anastrozole for the secondline treatment of advanced breast cancer in subgroups of postmenopausal women with visceral and non-visceral metastases: combined results from two multicentre trials. Eur J Cancer 2003;39:1228–33. 14. Ingle JN, Rowland KM, Suman VJ, et al. Evaluation of fulvestrant in women with advanced breast cancer and progression on prior aromatase inhibitor therapy: a phase II trial of the North Central Cancer Treatment Group. Breast Cancer Res Treat 2004;88(Suppl. 1):S38.. (abstr 409). 15. Perey L, Paridaens R, Nole ´ F, et al. Fulvestrant (Faslodexä) as hormonal treatment in postmenopausal patients with advanced breast cancer (ABC) progressing after treatment with tamoxifen and aromatase inhibitors: update of a phase II SAKK trial. Breast Cancer Res Treat 2004;88 (Suppl. 1): S236.. (abstr 6048). 16. Steger G, Bartsch R, Wenzel C, et al. Fulvestrant (FaslodexÒ) in metastatic breast cancer. Breast Cancer Res Treat 2003;82(Suppl. 1):S104.. (abstr 437). 17. Franco S, Perez A, Tan-Chiu E, Frankel C, Vogel CL. Response to fulvestrant in heavily pretreated postmenopausal women: a single-center experience. Breast Cancer Res Treat 2004;88:103–8. 18. Petruzelka L, Zimovjanova M, Konopasek B, Mares P, Dlouha Z. Fulvestrant in postmenopausal women with metastatic breast cancer progressing on prior endocrine therapy – updated results from an expanded access programme. Ann Oncol 2004;15(Suppl. 3):iii36.. (abstr 136P). 19. Jones SE, Pippen J, Webster A. A retrospective analysis of the proportion of patients responding for >1, 1.5 and 2 years in two phase III studies of fulvestrant versus anastrozole. Breast Cancer Res Treat 2004;88(Suppl. 1): S236.. (abstr 6047). 20. Houston SJ, Plunkett TA, Barnes DM, Smith P, Rubens RD, Miles DW. Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 1999;79:1220–6. 21. Dowsett M, Harper-Wynne C, Boeddinghaus I, et al. HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptorpositive primary breast cancer. Cancer Res 2001;61: 8452–8. 22. Menard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene 2003;22:6570–8. 23. Howell A. The future of fulvestrant (‘Faslodex’). Cancer Treatment Rev 2005;31(Suppl. 2):S26–33.