- Email: [email protected]
Should a biopsy be recommended to confirm metastatic disease in women with breast cancer?
Reflection and Reaction
Children’s Oncology Group (COG), is a second strategy that could improve outcome. By including re-induction treatment in the primary protocol, it should be possible to decrease or omit subsequent dexamethasone pulses, which were associated with some fatal infections and the development of osteonecrosis in ALL-9. Whether dexamethasone pulses have value in the context of re-induction treatment in contemporary trials for ALL remains to be determined. Several high-risk factors for bone marrow relapse were identified in the ALL-9 study: age 10 years and above, presenting leucocyte count 50×10⁹ cells per L or greater, T-cell immunophenotype, BCR–ABL1 positivity, and hypodiploidy. Again, several steps could be taken to improve outcome in this heterogeneous group of high-risk patients. The introduction of highdose dexamethasone during remission induction (10 mg/m² per day)4 or during post-remission treatment (12 mg/m² per day)3 improves outcome in T-cell ALL, especially for patients with a good early treatment response.3,4 In an ongoing trial at St Jude, we use highdose dexamethasone during remission induction and post-remission therapy for patients with high-risk T-cell ALL. A recent COG study showed an outstanding early outcome for patients with BCR–ABL1-positive ALL
treated with intensive chemotherapy and the addition of imatinib;5 longer follow-up is needed to determine whether this treatment improves the cure rate or merely prolongs remission duration.5 Finally, ongoing genomewide studies to identify genetic lesions with pathogenic significance in ALL, coupled with host pharmacogenetics, promise to yield new curative treatments for remaining groups of patients. Ching-Hon Pui St Jude Children’s Research Hospital and the University of Tennessee Health Science Center, Memphis, TN, USA [email protected] The author declared no conflicts of interest. 1
2
3 4
5
Veerman AJ, Kamps WA, van den Berg H, et al, for the Dutch Childhood Oncology Group. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997–2004). Lancet Oncol 2009; 10: 957–66. Pui C-H, Pei D, Sandlund JT, et al. Long-term results of St Jude Total Therapy studies 11, 12, 13A, 13B and 14 for childhood acute lymphoblastic leukemia. Leukemia (in press). Pui C-H, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–41. Schrappe M, Zimmermann M, Möricke A, et al. Dexamethasone in induction can eliminate one third of all relapses in childhood acute lymphoblastic leukemia (ALL): results of an international randomized trial in 3655 patients (trial AIEOP-BFM ALL 2000). Blood 2008; 112: 9 (abstr). Schultz KR, Bowman WP, Aledo A, et al. Improved early event free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children’s Oncology Group study. J Clin Oncol (in press).
Should a biopsy be recommended to confirm metastatic disease in women with breast cancer? Metastatic breast cancer is usually diagnosed by a combination of clinical and radiological findings. Once diagnosed, the choice of systemic therapy is based, in part, on the oestrogen receptor, progesterone receptor, and HER2 (also known as ERBB2) status from the patient’s primary breast tumour. The confirmatory biopsy of suspected metastatic lesions is rarely done. However, tumour characteristics such as hormone and HER2 receptor status can change. Indeed, discordance between the receptor status of primary and metastatic breast cancer has been described for over 30 years.1 The rate of such discordance in oestrogen and progesterone receptors can occur in as many as 40% of breast cancer cases.2 Discordance rates for HER2 status have also been described, but are less common.3 Over the past year, there has been increasing interest in the effect of this diswww.thelancet.com/oncology Vol 10 October 2009
cordance on therapeutic choices in advanced breast cancer and biopsy of metastatic disease is becoming a routine procedure in the management of advanced breast cancer. Confirmatory biopsies of metastatic disease have several proposed benefits for patient care. It is helpful in the confirmation (or occasionally exclusion) of advanced disease in patients who were previously not known to have metastases and who present with clinical or radiological evidence of solitary or oligo-metastatic disease. It might also be of assistance in individualising therapy based on the profile of metastatic disease rather than the primary tumour. Treatment decisions can be based on the receptor status of the disease that the patient has at the time, and not the receptor status of a surgical specimen that could have been taken many years previously. Other benefits might include improved selection of patients for targeted 933
Reflection and Reaction
Geoff Tompkinson/Science Photo Library
therapy trials, especially those that target the hormone or HER2 receptor in the metastatic setting. Many of the studies that have assessed discordance in hormone receptor and HER2 status between primary tumour and metastases have limitations. Most are retrospective, and are therefore liable to sampling bias. Other studies have used pathological techniques that have since been outdated, or used different laboratory techniques between primary tumour and metastatic tissues. We are aware of only two prospective studies in which women underwent biopsy of suspected metastatic lesions.4,5 Results showed changes in hormone receptor status in over 30% of patients and in HER2 status in 5–8% of patients. Interestingly, triple-negative tumours seemed to have the lowest discordance rate.5 More importantly, clinicians reported that information from metastatic biopsies altered the choice of therapy in more than one in eight cases. Improvements in interventional radiological techniques mean that most tissue is now accessible by minimally invasive methods. However, such techniques have weaknesses. The choice for the location of the biopsy is usually determined by the easiest or least invasive site, a process that can lead to sampling bias; especially in tumours that are significantly heterogeneous. Furthermore, bone is the most common site of metastasis in breast cancer, and biopsies of bone metastases provide a lower analysable yield for immunohistochemistry than other tissues.6 Any changes in receptor profile should be interpreted with caution owing to potential confounders. Clinicians tend to consider pathological reports as definitive, but variations in tissue processing can lead to erroneous results. False-negative results in oestrogen-receptor expression owing to inadequate fixation have been well described, and apply more to larger specimens than to core biopsies.7 Additionally, the deleterious effect of decalcification of bone or bone marrow stained for oestrogen receptor is another reason for poor antigen preservation.8 Even with adequate fixation and the avoidance of decalcification, inadequate sampling of a heterogeneous cancer can give misleading results. Consequently, there is a need for quality control to ensure consistent evaluation of oestrogen-receptor expression similar to recommendations for HER2.9,10 Even in the context of optimal tissue processing, the problems with false-negative results mean that gain of antigen (tumour changing from receptor negative to 934
positive) is likely to have a greater affect on treatment decisions than loss of antigen (tumour changing from receptor positive to negative). The biopsy of metastases might be associated with negative outcomes. Prospective data have shown that some women suffer pre-procedure anxiety, while post-procedural pain was reported by almost half of women. Overall, patients were satisfied with the biopsy procedure, although many expressed concern related to the time needed to obtain the biopsy and its results.4 Although there are no data to quantify factors such as anxiety, pain, and the effect of treatment delay, these aspects should be considered before undertaking such procedures. Finally, biopsy of metastatic lesions can be expensive, with substantial costs of interventional radiology and pathological evaluation. Alternatives to biopsy are the use of functional imagng, or the assessment of surrogates for metastatic disease, such as circulating tumour cells. 16α-[18]Fluoro-17βoestradiol (FES) is an oestrogen receptor ligand that can be used for the detection of oestrogen-receptor-positive malignant tumours such as breast cancer.11 Recent data have shown that the use of FES uptake and metabolic flare after an oestradiol challenge are both predictive of responsiveness to endocrine therapy in oestrogenreceptor-positive breast cancer.12 Unfortunately, despite isotopes having been developed for the functional assessment of both the oestrogen receptor and progesterone receptor, non-invasive methods to assess the expression of HER2 are at an early stage of development.13 Metastases have been shown to gain the expression of HER2,4,5 and HER2-directed therapy can have a substantial effect on metastatic disease. Therefore, while the use of functional imaging is exciting, it needs to be validated in larger prospective studies, and remains unavailable in the non-research setting in most centres. The assessment of circulating tumour cells in place of established metastatic disease is of interest; however, at present there are few data to support the use of these cells as surrogates for metastatic disease, and there is evidence that these cells can be highly heterogeneous in aetiology.14 A secondary benefit of tissue sampling, which cannot be replicated by non-invasive methods, is the ability to build biobanks of biopsy material taken from metastatic sites. Such biobanks will be valuable in translational studies, especially those that explore mechanisms of metastasis. Advancing such biomarker-driven www.thelancet.com/oncology Vol 10 October 2009
Reflection and Reaction
choice of treatment will depend on the availability of metastatic tissue. In conclusion, while decisions about whether or not to undertake a metastatic biopsy will usually be taken on the basis of a number of patient-related and tumourrelated factors, such as the natural history of the disease, timing of relapse and proposed treatment, the benefits of metastatic biopsy seem significant. The appropriate targeting of hormone and HER2 receptors is a cornerstone in the effective treatment in advanced breast cancer, and given the heterogeneity of metastatic breast cancer, offering patients the choice of a biopsy might ensure that the most appropriate targeted therapies are provided. This could also lead to an improvement in care. Indeed, prospective data show that a significant proportion of patients would be treated sub-optimally if therapy decisions were based solely on the receptor status of the primary breast tumour. Therefore, it seems appropriate for biopsies of metastatic lesions to be recommended, especially if these could affect the choice of treatment.
2
3
4
5
6
7
8 9
10
11
12
Eitan Amir*, Mark Clemons Division of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada (EA); Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada (MC) [email protected] The authors declared no conflicts of interest. 1
13
14
Li BD, Byskosh A, Molteni A, et al. Estrogen and progesterone receptor concordance between primary and recurrent breast cancer. J Surg Oncol 1994; 57: 71–77. Regitnig P, Schippinger W, Lindbauer M, et al. Change of HER-2/neu status in a subset of distant metastases from breast carcinomas. J Pathol 2004; 203: 918–26. Simmons C, Miller N, Geddie W, et al. Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol 2009; 20: 1499–504. Amir E, Freedman O, Simmons C, et al. Biopsy confirmation of metastatic breast cancer: interim results of a prospective biopsy study. Breast Cancer Res 2009; 11: S20. Amir E, Ooi WS, Simmons C, et al. Discordance between receptor status in primary and metastatic breast cancer: an exploratory study of bone and bone marrow biopsies. Clin Oncol (R Coll Radiol) 2008; 20: 763–68. Mann GB, Fahey VD, Feleppa F, et al. Reliance on hormone receptor assays of surgical specimens may compromise outcome in patients with breast cancer. J Clin Oncol 2005; 23: 5148–54. Bussolati G, Leonardo E. Technical pitfalls potentially affecting diagnoses in immunohistochemistry. J Clin Pathol 2008; 61: 1184–92. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25: 118–45. Yaziji H, Taylor CR, Goldstein NS, et al. Consensus recommendations on estrogen receptor testing in breast cancer by immunohistochemistry. Appl Immunohistochem Mol Morphol 2008; 16: 513–20. Peterson LM, Mankoff DA, Lawton T, et al. Quantitative imaging of estrogen receptor expression in breast cancer with PET and 18F-fluoroestradiol. J Nucl Med 2008; 49: 367–74. Dehdashti F, Mortimer JE, Trinkaus K, et al. PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat 2009; 113: 509–17. Dijkers EC, Kosterink JG, Rademaker AP, et al. Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging. J Nucl Med 2009; 50: 974–81. Müller V, Stahmann N, Riethdorf S, et al. Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res 2005; 11: 3678–85.
Brennan MJ, Donegan WL, Appleby DE. The variability of estrogen receptors in metastatic breast cancer. Am J Surg 1979; 137: 260–62.
Trials comparing cytology with human papillomavirus screening In a recent issue of The Lancet Oncology, Kitchener and colleagues1 published the first and second screening round results of the ARTISTIC trial, which compared cervical cancer screening using liquid-based cytology (LBC) with the combination of LBC and human papillomavirus (HPV) testing. The main purpose of this and other recent trials that have compared cytological screening with combined HPV and cytology was to show over time a reduced cumulative incidence of cervical intraepithelial neoplasia of grade 3 or worse (CIN3+) among women who tested negative for HPV at baseline compared with those who had normal cytology. This outcome was seen in all the randomised trials with www.thelancet.com/oncology Vol 10 October 2009
published longitudinal data.1–3 Less CIN3+ can be thought of as a proxy for a reduced incidence of invasive cervical cancer, and was proposed as one of the criteria for a possible switch in screening policy in European guidelines from cytology to HPV-based testing.4 These findings are also consistent with those from nonrandomised cohort studies that systematically showed a very low cumulative incidence of CIN3+ among women with a negative HPV test 5–10 years previously. In a large cluster-randomised trial in India, an even lower incidence of, and mortality from, invasive cervical cancer was shown in HPV-negative women (RR 0·47, 95% CI 0·32–0·69) for incidence of stage II cancer or worse, and 935
Children’s Oncology Group (COG), is a second strategy that could improve outcome. By including re-induction treatment in the primary protocol, it should be possible to decrease or omit subsequent dexamethasone pulses, which were associated with some fatal infections and the development of osteonecrosis in ALL-9. Whether dexamethasone pulses have value in the context of re-induction treatment in contemporary trials for ALL remains to be determined. Several high-risk factors for bone marrow relapse were identified in the ALL-9 study: age 10 years and above, presenting leucocyte count 50×10⁹ cells per L or greater, T-cell immunophenotype, BCR–ABL1 positivity, and hypodiploidy. Again, several steps could be taken to improve outcome in this heterogeneous group of high-risk patients. The introduction of highdose dexamethasone during remission induction (10 mg/m² per day)4 or during post-remission treatment (12 mg/m² per day)3 improves outcome in T-cell ALL, especially for patients with a good early treatment response.3,4 In an ongoing trial at St Jude, we use highdose dexamethasone during remission induction and post-remission therapy for patients with high-risk T-cell ALL. A recent COG study showed an outstanding early outcome for patients with BCR–ABL1-positive ALL
treated with intensive chemotherapy and the addition of imatinib;5 longer follow-up is needed to determine whether this treatment improves the cure rate or merely prolongs remission duration.5 Finally, ongoing genomewide studies to identify genetic lesions with pathogenic significance in ALL, coupled with host pharmacogenetics, promise to yield new curative treatments for remaining groups of patients. Ching-Hon Pui St Jude Children’s Research Hospital and the University of Tennessee Health Science Center, Memphis, TN, USA [email protected] The author declared no conflicts of interest. 1
2
3 4
5
Veerman AJ, Kamps WA, van den Berg H, et al, for the Dutch Childhood Oncology Group. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997–2004). Lancet Oncol 2009; 10: 957–66. Pui C-H, Pei D, Sandlund JT, et al. Long-term results of St Jude Total Therapy studies 11, 12, 13A, 13B and 14 for childhood acute lymphoblastic leukemia. Leukemia (in press). Pui C-H, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–41. Schrappe M, Zimmermann M, Möricke A, et al. Dexamethasone in induction can eliminate one third of all relapses in childhood acute lymphoblastic leukemia (ALL): results of an international randomized trial in 3655 patients (trial AIEOP-BFM ALL 2000). Blood 2008; 112: 9 (abstr). Schultz KR, Bowman WP, Aledo A, et al. Improved early event free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children’s Oncology Group study. J Clin Oncol (in press).
Should a biopsy be recommended to confirm metastatic disease in women with breast cancer? Metastatic breast cancer is usually diagnosed by a combination of clinical and radiological findings. Once diagnosed, the choice of systemic therapy is based, in part, on the oestrogen receptor, progesterone receptor, and HER2 (also known as ERBB2) status from the patient’s primary breast tumour. The confirmatory biopsy of suspected metastatic lesions is rarely done. However, tumour characteristics such as hormone and HER2 receptor status can change. Indeed, discordance between the receptor status of primary and metastatic breast cancer has been described for over 30 years.1 The rate of such discordance in oestrogen and progesterone receptors can occur in as many as 40% of breast cancer cases.2 Discordance rates for HER2 status have also been described, but are less common.3 Over the past year, there has been increasing interest in the effect of this diswww.thelancet.com/oncology Vol 10 October 2009
cordance on therapeutic choices in advanced breast cancer and biopsy of metastatic disease is becoming a routine procedure in the management of advanced breast cancer. Confirmatory biopsies of metastatic disease have several proposed benefits for patient care. It is helpful in the confirmation (or occasionally exclusion) of advanced disease in patients who were previously not known to have metastases and who present with clinical or radiological evidence of solitary or oligo-metastatic disease. It might also be of assistance in individualising therapy based on the profile of metastatic disease rather than the primary tumour. Treatment decisions can be based on the receptor status of the disease that the patient has at the time, and not the receptor status of a surgical specimen that could have been taken many years previously. Other benefits might include improved selection of patients for targeted 933
Reflection and Reaction
Geoff Tompkinson/Science Photo Library
therapy trials, especially those that target the hormone or HER2 receptor in the metastatic setting. Many of the studies that have assessed discordance in hormone receptor and HER2 status between primary tumour and metastases have limitations. Most are retrospective, and are therefore liable to sampling bias. Other studies have used pathological techniques that have since been outdated, or used different laboratory techniques between primary tumour and metastatic tissues. We are aware of only two prospective studies in which women underwent biopsy of suspected metastatic lesions.4,5 Results showed changes in hormone receptor status in over 30% of patients and in HER2 status in 5–8% of patients. Interestingly, triple-negative tumours seemed to have the lowest discordance rate.5 More importantly, clinicians reported that information from metastatic biopsies altered the choice of therapy in more than one in eight cases. Improvements in interventional radiological techniques mean that most tissue is now accessible by minimally invasive methods. However, such techniques have weaknesses. The choice for the location of the biopsy is usually determined by the easiest or least invasive site, a process that can lead to sampling bias; especially in tumours that are significantly heterogeneous. Furthermore, bone is the most common site of metastasis in breast cancer, and biopsies of bone metastases provide a lower analysable yield for immunohistochemistry than other tissues.6 Any changes in receptor profile should be interpreted with caution owing to potential confounders. Clinicians tend to consider pathological reports as definitive, but variations in tissue processing can lead to erroneous results. False-negative results in oestrogen-receptor expression owing to inadequate fixation have been well described, and apply more to larger specimens than to core biopsies.7 Additionally, the deleterious effect of decalcification of bone or bone marrow stained for oestrogen receptor is another reason for poor antigen preservation.8 Even with adequate fixation and the avoidance of decalcification, inadequate sampling of a heterogeneous cancer can give misleading results. Consequently, there is a need for quality control to ensure consistent evaluation of oestrogen-receptor expression similar to recommendations for HER2.9,10 Even in the context of optimal tissue processing, the problems with false-negative results mean that gain of antigen (tumour changing from receptor negative to 934
positive) is likely to have a greater affect on treatment decisions than loss of antigen (tumour changing from receptor positive to negative). The biopsy of metastases might be associated with negative outcomes. Prospective data have shown that some women suffer pre-procedure anxiety, while post-procedural pain was reported by almost half of women. Overall, patients were satisfied with the biopsy procedure, although many expressed concern related to the time needed to obtain the biopsy and its results.4 Although there are no data to quantify factors such as anxiety, pain, and the effect of treatment delay, these aspects should be considered before undertaking such procedures. Finally, biopsy of metastatic lesions can be expensive, with substantial costs of interventional radiology and pathological evaluation. Alternatives to biopsy are the use of functional imagng, or the assessment of surrogates for metastatic disease, such as circulating tumour cells. 16α-[18]Fluoro-17βoestradiol (FES) is an oestrogen receptor ligand that can be used for the detection of oestrogen-receptor-positive malignant tumours such as breast cancer.11 Recent data have shown that the use of FES uptake and metabolic flare after an oestradiol challenge are both predictive of responsiveness to endocrine therapy in oestrogenreceptor-positive breast cancer.12 Unfortunately, despite isotopes having been developed for the functional assessment of both the oestrogen receptor and progesterone receptor, non-invasive methods to assess the expression of HER2 are at an early stage of development.13 Metastases have been shown to gain the expression of HER2,4,5 and HER2-directed therapy can have a substantial effect on metastatic disease. Therefore, while the use of functional imaging is exciting, it needs to be validated in larger prospective studies, and remains unavailable in the non-research setting in most centres. The assessment of circulating tumour cells in place of established metastatic disease is of interest; however, at present there are few data to support the use of these cells as surrogates for metastatic disease, and there is evidence that these cells can be highly heterogeneous in aetiology.14 A secondary benefit of tissue sampling, which cannot be replicated by non-invasive methods, is the ability to build biobanks of biopsy material taken from metastatic sites. Such biobanks will be valuable in translational studies, especially those that explore mechanisms of metastasis. Advancing such biomarker-driven www.thelancet.com/oncology Vol 10 October 2009
Reflection and Reaction
choice of treatment will depend on the availability of metastatic tissue. In conclusion, while decisions about whether or not to undertake a metastatic biopsy will usually be taken on the basis of a number of patient-related and tumourrelated factors, such as the natural history of the disease, timing of relapse and proposed treatment, the benefits of metastatic biopsy seem significant. The appropriate targeting of hormone and HER2 receptors is a cornerstone in the effective treatment in advanced breast cancer, and given the heterogeneity of metastatic breast cancer, offering patients the choice of a biopsy might ensure that the most appropriate targeted therapies are provided. This could also lead to an improvement in care. Indeed, prospective data show that a significant proportion of patients would be treated sub-optimally if therapy decisions were based solely on the receptor status of the primary breast tumour. Therefore, it seems appropriate for biopsies of metastatic lesions to be recommended, especially if these could affect the choice of treatment.
2
3
4
5
6
7
8 9
10
11
12
Eitan Amir*, Mark Clemons Division of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada (EA); Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada (MC) [email protected] The authors declared no conflicts of interest. 1
13
14
Li BD, Byskosh A, Molteni A, et al. Estrogen and progesterone receptor concordance between primary and recurrent breast cancer. J Surg Oncol 1994; 57: 71–77. Regitnig P, Schippinger W, Lindbauer M, et al. Change of HER-2/neu status in a subset of distant metastases from breast carcinomas. J Pathol 2004; 203: 918–26. Simmons C, Miller N, Geddie W, et al. Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol 2009; 20: 1499–504. Amir E, Freedman O, Simmons C, et al. Biopsy confirmation of metastatic breast cancer: interim results of a prospective biopsy study. Breast Cancer Res 2009; 11: S20. Amir E, Ooi WS, Simmons C, et al. Discordance between receptor status in primary and metastatic breast cancer: an exploratory study of bone and bone marrow biopsies. Clin Oncol (R Coll Radiol) 2008; 20: 763–68. Mann GB, Fahey VD, Feleppa F, et al. Reliance on hormone receptor assays of surgical specimens may compromise outcome in patients with breast cancer. J Clin Oncol 2005; 23: 5148–54. Bussolati G, Leonardo E. Technical pitfalls potentially affecting diagnoses in immunohistochemistry. J Clin Pathol 2008; 61: 1184–92. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25: 118–45. Yaziji H, Taylor CR, Goldstein NS, et al. Consensus recommendations on estrogen receptor testing in breast cancer by immunohistochemistry. Appl Immunohistochem Mol Morphol 2008; 16: 513–20. Peterson LM, Mankoff DA, Lawton T, et al. Quantitative imaging of estrogen receptor expression in breast cancer with PET and 18F-fluoroestradiol. J Nucl Med 2008; 49: 367–74. Dehdashti F, Mortimer JE, Trinkaus K, et al. PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat 2009; 113: 509–17. Dijkers EC, Kosterink JG, Rademaker AP, et al. Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging. J Nucl Med 2009; 50: 974–81. Müller V, Stahmann N, Riethdorf S, et al. Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res 2005; 11: 3678–85.
Brennan MJ, Donegan WL, Appleby DE. The variability of estrogen receptors in metastatic breast cancer. Am J Surg 1979; 137: 260–62.
Trials comparing cytology with human papillomavirus screening In a recent issue of The Lancet Oncology, Kitchener and colleagues1 published the first and second screening round results of the ARTISTIC trial, which compared cervical cancer screening using liquid-based cytology (LBC) with the combination of LBC and human papillomavirus (HPV) testing. The main purpose of this and other recent trials that have compared cytological screening with combined HPV and cytology was to show over time a reduced cumulative incidence of cervical intraepithelial neoplasia of grade 3 or worse (CIN3+) among women who tested negative for HPV at baseline compared with those who had normal cytology. This outcome was seen in all the randomised trials with www.thelancet.com/oncology Vol 10 October 2009
published longitudinal data.1–3 Less CIN3+ can be thought of as a proxy for a reduced incidence of invasive cervical cancer, and was proposed as one of the criteria for a possible switch in screening policy in European guidelines from cytology to HPV-based testing.4 These findings are also consistent with those from nonrandomised cohort studies that systematically showed a very low cumulative incidence of CIN3+ among women with a negative HPV test 5–10 years previously. In a large cluster-randomised trial in India, an even lower incidence of, and mortality from, invasive cervical cancer was shown in HPV-negative women (RR 0·47, 95% CI 0·32–0·69) for incidence of stage II cancer or worse, and 935