University of Groningen Imaging hormone receptors in metastatic breast cancer patients Venema, Clasina Marieke

(1)

Imaging hormone receptors in metastatic breast cancer patients

Venema, Clasina Marieke

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date: 2018

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Venema, C. M. (2018). Imaging hormone receptors in metastatic breast cancer patients. Rijksuniversiteit Groningen.

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

(2)

517613-L-sub01-bw-Venema 517613-L-sub01-bw-Venema 517613-L-sub01-bw-Venema 517613-L-sub01-bw-Venema Processed on: 7-3-2018 Processed on: 7-3-2018 Processed on: 7-3-2018

Processed on: 7-3-2018 PDF page: 221PDF page: 221PDF page: 221PDF page: 221

Chapter 10

(3)

222

SUMMARY

The expression of estrogen receptors (ER) is a well-established predictive and prognostic biomarker in breast cancer. Several drugs are available targeting this receptor leading to overall survival benefit in a large subgroup of breast cancer patients. One of the current challenges in oncology lies in identifying the best therapy for the individual patient. Assessment of ER expression in breast cancer or metastasis is an essential first step in this setting. For the primary tumor, determination of ER level can be performed easily, as the standard work-up for primary breast cancer includes a biopsy or surgical excision (1). The tissue sample can be stained immunohistochemically to identify tumor characteristics such as the presence of ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Based on these staining results, in combination with patient characteristics, tumor size and proliferation index or molecular profiling, the most optimal adjuvant treatment can be determined (2). However, not all patients can be cured and metastatic breast cancer still occurs in ~20 percent of the patients (3). A factor that plays a role in this setting is treatment resistance, for instance to hormonal treatment due to loss of ER. This makes it imperative to collect the most recent information on tumor characteristics before each new line of treatment, for instance through assessment of fresh tissue samples.

Biopsies of metastases are not always feasible in a patient, as the lesion may be inaccessible or may be considered unsafe to biopsy. And if only one lesion is biopsied, heterogeneity of tumor characteristics on various lesions throughout the body is still unknown. In vivo imaging of hormone receptors has the potential to guide clinical decision making. The UMCG has obtained extensive experience with the ER tracer 18F-fluoroestradiol (FES). The FES PET scan is currently available for clinicians as a tool to gain additional disease information, in case regular work up provides insufficient information to base treatment decisions upon. For prediction of treatment response FES PET might have additional value.

Although the ER is an established biomarker in breast cancer, the search for new biomarkers and drug targets continues, and as such the androgen receptor (AR) is of interest. The role of this receptor in breast cancer is not as clear as that of the ER, but is well established in patients with prostate cancer.

(4)

223

This receptor can be visualized by PET with the tracer 16β-18 F-fluoro-5α-dihydrotestosterone (FDHT).

The aim of this thesis was to determine the use of hormone receptor imaging

via FES PET and FDHT PET scans in breast cancer patients and to evaluate the ability of PET with these tracers to predict therapy outcome.

Chapter 1 includes a short introduction and outline of the thesis.

In Chapter 2 we described recommendations on the use and interpretation of FES PET scans. After the University Medical Center Groningen has implemented the FES PET in patients with a clinical dilemma, we have performed at least 50 FES PET scans a year for clinical use. In this chapter, we described the technical aspects of the FES PET scan that can be used as a first recommendation paper. The ultimate goal is to eventually implement this technique in guidelines and to make this technique accessible for all large hospitals in the Netherlands and even worldwide.

The previous experience with FES PET has also drawn our attention to occasional FES uptake in the lungs, in the absence of a tumor substrate. We hypothesized that this non-tumor uptake could be a local reaction to radiation therapy. In the retrospective analysis described in Chapter 3, we compared FES PET scans in 70 patients that were irradiated on the thorax, with those in a control group of 39 patients that never received radiation therapy. We found that 39 out of 70 patients that were irradiated had non-tumor FES uptake in the lungs versus 9 out of 38 patients that were not irradiated. Post-irradiation non-tumor FES uptake in the lungs could be related to the fibrosis and inflammation, that occurs after radiation therapy in patients. Seven out of the nine patients that did show enhanced uptake without previous irradiation, showed fibrosis on the CT scan. Fibrosis and inflammation both express the ER isoform β to which the FES tracer also binds, though with a lower affinity compared to the ERα. This could imply that enhanced FES uptake might be specific but non-tumor related. This implies that for interpreting FES uptake, information on radiation history and other causes for fibrosis should be taken into consideration by nuclear medicine physicians.

In Chapter 4 we showed that FES PET had added value in 4 patients with lobular breast cancer, in which conventional imaging was inconclusive. Lobular

(5)

224

breast cancer is notoriously difficult to detect and evaluate with conventional imaging, and the use of FES PET could be of importance in this subset of breast cancer patients. Based on these results, a prospective multicenter trial may be conducted to evaluate the added value of FES PET/CT for diagnosis, staging and therapy decision-making in a large cohort of patients with lobular breast cancer.

Chapter 5 describes the use of FES PET as a potential biomarker for response

to treatment with palbociclib in addition to letrozole. While in general, this treatment option has improved progression free survival in patients with ER positive metastatic breast cancer, not every patient benefits from this new approach. In addition, the physical toxicity and financial burden of this combination treatment can be considerable. It is therefore of great importance to predict treatment response, to allow optimal selection of patients. We hypothesized that assessment of tumor characteristics within an individual patient might support response prediction. We performed a per lesion analysis in 14 patients and in total 279 lesions were used for analysis. In this feasibility trial, low FES uptake on FES PET in metastatic breast cancer lesions was related to a lack of response and early progression on letrozole and palbociclib treatment, particularly in visceral lesions. FES-PET may therefore be a potential biomarker for whole body response to this combination treatment. FES PET also allowed to analyze each lesion individually and gave insight in ER heterogeneity within a patient. This could potentially help in treating patients on a lesion based approach. This will have to be confirmed in future clinical trials.

In Chapter 6 we reviewed the androgen receptor as a target in breast cancer patients. Preclinical and clinical data showed different roles in the different breast cancer subtypes. In addition, we performed an in silico analysis of more than 7000 primary breast cancer samples, available in the public domain. This allowed us to further investigate the role of AR in the different breast cancer subtypes. We found that especially in the HER2 positive group, AR expression was associated with worse disease free survival.

As molecular imaging of the AR by means of FDHT PET has not been applied in breast cancer patients so far, this was the objective of the pilot study described in Chapter 7. FHDT uptake in a metastatic lesion was correlated to AR expression measured by immunohistochemistry, in the same lesion.

(6)

225

Similarly this was done for FES uptake and ER expression in the same patients. A total of 13 patients were included. We found a good correlation between both AR expression and FDHT uptake, as well as ER expression and FES uptake. The optimal cutoff for AR-positive lesions was a maximum standardized uptake value (SUVmax) of 1.9 for FDHT-PET, yielding a sensitivity of 91% and a

specificity of 100%. For FES PET an optimal cutoff SUVmax of 1.5 resulted in a

sensitivity and specificity of 100% for ER in this group of patients. These results emphasize the potential use of whole-body imaging for receptor status assessment, particularly in view of biopsy-associated sampling errors and heterogeneous receptor expression in breast cancer metastases.

In Chapter 8 we evaluated whether the effect of the AR blocker bicalutamide could be visualized by means of FDHT PET prior to and during treatment. In this pilot study, it was shown that bicalutamide treatment indeed decreased FDHT uptake in 6 out of 8 patients. Larger, prospective studies should be conducted to analyze the positive predictive value of serial FDHT PET scanning in patients with metastatic breast cancer treated with AR targeted therapies. Over 30 different PET tracers are currently under investigation in breast cancer alone and many more are expected. Nonetheless, only FDG PET is incorporated in the breast cancer guidelines at present. In Chapter 9 we summarized the steps from pre-clinical to first-in-human molecular imaging studies, and summarized research on PET tracers and described potential steps to implement more PET tracers into clinical practice. It requires multidisciplinary efforts and sharing of data. Data collection and scanning procedures should be more harmonized to build an incremental warehouse. The data in this warehouse could then guide optimal application, and eventually provide sufficient level of evidence to implement tracers in clinical practice.

FUTURE PERSPECTIVES

Molecular imaging of hormone receptors in breast cancer, is on its way to claim a place in clinical practice. A number of important steps in this process have been described in the present thesis, such as the concordance between immunohistochemical findings and hormone receptor PET scans (Chapter 7). In case of a clinical dilemma, the FES PET is already available as a tool that provides additional information beyond regular work up, and that could

(7)

226

support clinical decision making (Chapter 4). Per lesion analysis on hormone receptor PET scans indicates considerable within-patient heterogeneity, which likely affects treatment response (Chapters 5, 8). However it is clear that, prior to further implementation of these novel techniques in routine clinical practice, additional steps are needed (Chapter 2, 9).

Towards possible implementation: as the previous studies performed were

relatively small, larger trials are needed to establish the place of molecular imaging as a biomarker for prognosis or response. Doing so will define the clinical utility of the technique. A prospective, multicenter trial is currently ongoing, where the FES PET results are part of the treatment decision process in 200 patients with newly diagnosed metastatic breast cancer, and correlated to survival (NCT01957332). Next to the FES PET, also imaging of the HER2 expression is evaluated with 89Zr-trastuzumab-PET in this trial. Furthermore, results of early FDG PET (after 2 weeks of treatment), tumor biopsies and circulating tumor DNA are evaluated to see whether these techniques can guide personalized therapy. Also standardization of techniques and scan interpretation is crucial in this Dutch multicenter trial. The results of this trial are pivotal for a potential implementation of these imaging techniques as a biomarker in the work up of metastatic breast cancer. With regard to the FDHT PET in breast cancer patients, larger confirmatory studies should be conducted to further validate the cut-off value for FDHT uptake for AR positivity. Currently, different cut-off values for AR positivity are used in literature, and it remains unclear which threshold is relevant for AR targeted therapies.

Whether serial scanning provides additional value with regard to treatment response and drug dosing is another issue to be addressed. Previously, van Kruchten et al. showed that incomplete reduction in ER availability by the ER degrader fulvestrant was associated with early progression (5). Another feasibility trial with a novel ER degrader, Rad1901, used serial FES PET in an dose-de-escalation study (NCT02650817). This study showed that even at lower doses, with less toxicity, the binding capacity of the ER could be completely blocked (6). Future studies could address whether dosing could be individualized based on imaging results.

(8)

227

Innovation through novel tracer development. This could involve new tracers

for well-known targets in breast cancer. For example using 4-fluoro-11β-methoxy-16α-[18F]fluoroestradiol (4FMFES) resulted in a higher tumor contrast compared to FES (4). In addition, imaging of the PR, is potentially of clinical relevance. By means of 18F-Fluoro-16,17-[(r)-(10-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione (18F-FFNP), 15/16 PR positive breast cancers were successfully identified (7). The therapeutic role of the PR as sole target in breast cancer is unclear but PR is often co-expressed with the ER. PR is an estrogen responsive gene, and PR expression could be a biomarker for ER activation.

Novel tracers for possible new targets include tracers developed against ER β. This receptor is present in several breast cancer in several breast cancer subtypes, and is also expressed in up to 80% of the triple negative breast cancer. The ER β is also expressed in other types of cancer such as prostate and ovarian cancer. Imaging these receptors is in the preclinical phase, and the clinical role is not clear to date (8).

Other new targets that are used in prostate cancer patients can also have potential use in breast cancer patients. The prostate cancer specific membrane antigen (PSMA) is specifically expressed in prostate cancer and has no expression in healthy tissue. The PSMA can be visualized with a fluor-18 PSMA tracer as well as with a gallium-68 (68Ga-PSMA) (9). In prostate cancer patients several studies have been performed and showed that it was feasible to identify metastases of prostate cancer more accurate than with 18F-choline PET (10). The presence of PSMA is also described in breast cancer patients and 68Ga-PSMA-Pet showed uptake in 84% of the breast cancer metastases (11). Based on a retrospective study, targeting the PSMA in prostate cancer by means of radionuclide therapy with 177Lu-PSMA has also proven efficacy, with low grade toxicity profiles (12). This could also be a potential treatment option in patients with PSMA expressing metastatic breast cancer lesions. To analyze this, further research is necessary to determine the PSMA levels in breast cancer lesions and healthy tissue. If it is feasible to visualize the PSMA in breast cancer lesions with no or low uptake in healthy tissue, further studies can explore the effects of 177Lu-PSMA therapy.

(9)

228

Innovation through new techniques: nuclear imaging has high specificity, but

radiation burden limits it use. Due to the shorter physical half-lifes, tracers labeled with 18F or 68Ga have a lower radiation burden than 89Zr-labelled tracers. Yet, even for short-lived PET tracers, radiation exposure can still be a hurdle, especially in study designs with serial PET scans and/or PET scans combined with diagnostic CT scans for example in the adjuvant setting.

Besides molecular imaging strategies other markers are also of interest. Circulating tumor DNA has the advantage to detect mutations and is easily collected. Combining multiple biomarkers is likely to give complementary insight in tumor characteristics within one patient. In this regard cost aspects should naturally be considered also.

In conclusion: imaging of hormone receptors in breast cancer is promising, and

has the potential to contribute to precision medicine. To implement these imaging techniques in breast cancer management, the results of larger trials regarding clinical utility are required. Data from different trials should be combined to provide solid evidence. Implementation can then be initiated with regard to the production facilities and tracer distribution networks, and thereafter the process can be expanded to hospitals within traveling distance for the tracer transport. In the Netherlands this could easily result in a 100% coverage.

(10)

229

REFERENCES:

1.

World Health Organization, www.who.int/cancer, accessed May 2017

2.

National Comprehensive Cancer Network: Clinical practice guidelines in oncology; breast cancer version 1. Accessed: May 2017

3.

Early breast cancer trialists collaborative group (EBCTCG) effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomised trials. Lancet 2005;365:1687-1717

4.

Paquette M, Lavellée É, Phoenix S et al. Improved Estrogen Receptor Assessment by PET Using the Novel Radiotracer 4FMFES in ER+ Breast Cancer Patients: an Ongoing Phase II Clinical Trial. J Nucl Med 2017;doi:10.2967

5.

Van Kruchten M, de Vries EGE, Glaudemans AWJM et al. Measuring residual estrogen receptor availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Disc 2015;5:72-81

6.

De Vries EGE, Venema CM, Glaudemans AWJM et al. A Phase 1 study of RAD1901, an oral selective estrogen receptor degrader, in ER positive, HER2 negative, advanced breast cancer patients. J Clin Oncol 2016; 34:suppl TPS627

7.

Dehdashti F, Laforest R, Gao F et al. Assessment of progesterone receptors in breast carcinoma by PET with 21–18F-Fluoro-16_,17_-[(r)-(10-_-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione. J Nucl Med 2012;53:363–370

8.

Antunes IF, van Waarde A, Dierckx RA, de Vries EG, Hospers GA, de Vries EF. Synthesis and Evaluation of the Estrogen Receptor β-Selective Radioligand 2-18F-Fluoro-6-(6-Hydroxynaphthalen-2-yl)Pyridin-3-ol: Comparison with 16α-18F-Fluoro-17β-Estradiol. J Nucl Med 2017;58:554-559

9.

Afshar-Oromieh A, Haberkorn U, Eder M, Eisenhut M, Zechmann CM. [68GA]gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH. Eur J Nucl Med Mol Imaging 2012;39:1085-1086

10.

O’Keefe DS, Su SL, Bacich DJ et al. Mapping, genomic organization and promoter analysis of the human prostate-specific membrane antigen gene. Biochim Biophys Acta. 1998;1443:113-127.

11.

Sathekge M, Modiselle M, Vorster M et al. 68Ga-PSMA imaging of metastatic breast cancer. Eur J Nucl Med Mol Imaging 2015;42:1482-1483

(11)

230

12.

Fendler WP, Reinhardt S, Ilhan H et al. Preliminary experience with dosimetry, response and patient reported outcome after 177Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer. Oncotarget 2017;10:3581-3590.

(12)

(13)