Discordance in hormone receptor status in breast cancer during tumour progression Eva Karlsson (1,2) Linda Lindström (1) Ulla Wilking (1) Lambert Skoog

Discordance in hormone receptor status in breast cancer during tumour progression

Eva Karlsson (1,2) Linda Lindström (1) Ulla Wilking (1) Lambert Skoog (3) Ulla Johansson (4) Jonas Bergh (1,5)

1. Department of Oncology and Pathology Cancer Center KarolinskaKarolinska Institutet ,Stockholm, Sweden,

2. Department of Oncology Karlstad Hospital,Sweden3. Department of Pathology/Cytology Karolinska University Hospital

4. Center of Oncology Stockholm5. Dept of Medical Oncology,The Christie,Manchester University/Paterson Institute, UK


Background

• Today therapy management of breast cancer relapse is almost always based of primary tumour characteristics such as ER / PR and HER2 status, sites of relapse and relapse free survival time

• Diagnosis of breast cancer relapse is therefore based on a combination of clinical and radiological examinations

• In rare instances image diagnosis of relapse may actually represent a benign lesion or a new primary cancer or metastases from another malignancy


Background• Lack of stability in hormone receptors between primary breast cancer and

corresponding relapse have been reported• Despite repeated observations, management of metastatic breast cancer patients has

essentially been unchanged and based on primary tumour characteristics

Estrogen receptor status in primary breast cancers compared with the corresponding relapses

Publication / Abstract Patients Discordant Patients

Author Number Percent

Liedtke et al, 2009 Ann Oncol 228 18,4

Broom et al, 2009 Anticancer Res 62 17,7

Simmons et al, 2009 Ann Oncol 25 40

Amir et al, 2008 Clin Oncol 9 55,6

Guarneri et al, 2008 The Oncologist 75 22,7

Wu et al, 2008 Clin Cancer Res 10 20

Lower et al, 2005 Breast Res Treat 200 30

Wang et al, 2004 Ai Zheng 65 35,4

Nedergaard et al, 1995 APMIS 101 20,8

Kamby et al, 1989 Br J Cancer 62 37,1


Aims• Determine if hormone receptors (ER / PR) change between primary breast

cancer and recurrence

Material and method

• 1095 breast cancer patients in Stockholm who relapsed during 1997-2007

• All available information on these individuals were requested from the Center of Oncology Stockholm

• Primary cancers and corresponding relapses were retrospectively compared for hormonal receptor status


Material and methods

• Hormone receptor data were manually collected from the original pathology reports

We gave first priority to immunohistochemistry (IHC) for ER/PR, if not available we used immunocytochemistry (ICC) from the cytology aspirates, which routinely is performed and if not available we used biochemical receptor determination

• Aspiration cytology was originally invented and described at Karolinska Hospital some 50 years ago. The technique requires considerable manual skills and is at Karolinska only practiced by a few very experienced cytopathologist performing the tumour aspirations and they have developed the techniques for ICC for ER, initially in parallel with the biochemical receptor determinations.

• This retrospective study was approved by the Ethical committee at the Karolinska Institutet


Results

• In 486 patients ER information were available from both primary and one or more recurrent sites resulting in 679 patients pairs

ER changed in 27% from positive in primary tumour to negative in relapse and 8% changed from negative to positive

• In 456 patients PR information were available from both primary and one or more recurrent sites resulting in 630 patients pairs

PR status changed in 38% from positive in primary tumour to negative in relapse and 5% changed from negative to positive

Overall breast cancer survival from the time of primary tumour diagnosis to death or censoring contrasting intra-individual ER status in primary tumour and relapse (both local and systemic relapses included)

Overall breast cancer survival from the time of primary tumour diagnosis to death or censoring contrasting intra-individual ER status in primary tumour and relapse (both local and systemic relapses included)

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Prim(+)-Rel(+)

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log rank p<0.0001

Numbers at risk Prim(+)-Rel(+) 213 207 189 150 131 96 Prim(+)-Rel(-) 123 116 86 69 52 41 Prim(-)-Rel(+) 32 28 25 18 13 11 Prim(-)-Rel(-) 109 93 54 37 25 15

Overall breast cancer survival from the time of relapse diagnosis to death or censoring contrasting intra-individual ER status in primary tumour and relapse (both local and systemic relapses included)

Overall breast cancer survival from the time of relapse diagnosis to death or censoring contrasting intra-individual ER status in primary tumour and relapse (both local and systemic relapses included)

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Numbers at risk Prim(+)-Rel(+) 213 125 71 44 18 8 Prim(+)-Rel(-) 123 61 40 20 6 2 Prim(-)-Rel(+) 32 19 10 3 1 0 Prim(-)-Rel(-) 109 55 26 15 6 0

Risk of death depending on intra-individual ER status in primary tumour and relapse

Intra-individual primary tumour and relapse Patients Deaths

Overall survival from

breast cancer diagnosis to death or censoring

Overall survival from breast cancer relapse to death or censoring

ER status Number OverallAdjusted*

HR (95% CI)Adjusted*

HR (95% CI)Local and systemic relapsePrim(+)/Rel(+) 217 93 1.0 ref. 1.0 ref.Prim(+)/Rel(-) 125 66 1.49 (1.05-2.11) 1.27 (0.90-1.81)Prim(-)/Rel(+) 33 12 0.86 (0.43-1.69) 0.89 (0.45-1.77)Prim(-)/Rel(-) 109 55 1.26 (0.79-2.00) 0.97 (0.61-1.55)

Systemic relapsePrim(+)/Rel(+) 145 57 1.0 ref. 1.0 ref.Prim(+)/Rel(-) 108 63 1.91 (1.29-2.84) 1.26 (0.84-1.89)Prim(-)/Rel(+) 23 9 1.38 (0.64-2.97) 1.11 (0.51-2.41)Prim(-)/Rel(-) 82 46 1.89 (1.09-3.28) 1.22 (0.70-2.12)

Risk of death in breast cancer patients depending on intra-individual ER status in primary tumour and relapse

*Adjusted for age and calender year of diagnosis, progesterone receptor,tumour classification,tumour stage,lymph node metastasis, hormonal treatment and chemotherapy


Methodological issues

• Our results are based on both biochemical receptor determinations and IHC/ICC with very similar data for concordant and discordant use of the methods, respectively

• The concordance between the biochemical and IHC/ ICC methods are high (ER 82% to 93%)

• New data at Departement of Pathology/Cytology Karolinska from 683 breast cancer patients with ER status from both IHC and biochemical methodes , and the concordance between them was high 88% ( manuscript Mahmoud R. Khoshnoud et al)

• The pathology laboratory at Karolinska University Hospital has continuously participated in quality assurance programmes for receptor analyses, both during the era of biochemical determinations and the present IHC/ICC techniques and all these different techniques were run parallel for years

The usage of the different methods will therefore likely not explain our findings

ER*Status Number PercentConcordant techniques Prim-MetPrim(+)/Met(-) 72 26,8Prim(-)/Met(+) 17 6,3

Discordant techniques Prim-MetPrim(+)/Met(-) 114 28,2Prim(-)/Met(+) 34 8,4*Cut-off value of 0.05 fmol/µg DNA and 10%, for monoclonal antibody based biochemical and IHC/ICC methods, respectively


Potential shortcomings

• This study is retrospective with retrospectively collected information on hormonal receptor status

• Hormone receptor data were manually collected from the original pathology reports

We gave first priority to immunohistochemistry (IHC ) for ER/PR, if not available we used immunocytochemistry (ICC) from the cytology aspirates, which routinely is performed and if not available we used biochemical receptor determination

• On one hand as for all immunohistochemical / immunocytochemical techniques, they may be falsely negative and positive on the other hand not systematically in one direction


Conclusions

• Biopsy of a suspected ”metastatic” breast cancer lesion will improve the diagnostic precision, for single patients offer alternative/better therapies and even occasionally exclude recurrent breast cancer

• Nearly every third patient with breast cancer change hormone receptor status during tumour progression

• Increased risk of dying were seen in patients loosing ER during tumour progression compared with stable ER positive patients

• Therapy management of metastatic disease is suboptimal when only based on primary tumour characteristics

Our data together with multiple small and retrospective data even from a prospective study (Simmons et al 2009 Ann Oncol) underlines the needs for practice change


“Put simply, failure to biopsy recurrent or metastatic breast cancer carries a significant risk that our management is inadequately informed and may be inappropriate”

(Sharma et al Nature Reviews Clinical Oncology 2010)

Acknowledgement

All the patientsThe clinical colleagues at Karolinska who had high ambitions in aiming at securing the “correct” diagnosis of the breast cancer patients at time of clinically and radiologically (suspected) relapse

Anders Höög (Karolinska), Anna-Lena Borg (CCK), Torsten Hägerström (CCK) Mikael Bergenheim (Karlstad Hospital) Sten-Åke Lindahl (Karlstad Hospital) Bo Nordenskjöld (Linköping University Hospital) Elisabet Lidbrink (Karolinska University Hospital)

The Swedish Breast Cancer Association (BRO), FOU Värmland

Jonas Bergh’s research group is supported by grants from the Swedish Cancer Society, the Stockholm Cancer Society, the King Gustav V Jubilee Fund, the Swedish Research Council, the Stockholm City Council, Karolinska Institutet and Stockholm County Council Research Strategy Committee, The Swedish Breast Cancer Association (BRO), the Karolinska Institutet Research Funds, Manchester University, Christie Hospital & Paterson Institute and Märit and Hans Rausing´s Initiative against Breast Cancer


The reported switch of hormonal receptors may partly represent

• tumour progression and selection

• influence from the microenvironment

• intratumour heterogeneity

• influence by given therapy

• methodological shortcomings regarding

receptor determination


Relapse sites stratified on relapse ER status

Site of Total Totalrelapse ICD-9 Number Percent Number Percent Number Number Percent Number Percent NumberAll sites 407 48.5 432 51.5 839 596 73,2 218 26,8 814

Local relapse 1741,1742 95 23.3 150 34.7 245 146 24,5 92 42,2 238Lymph node 1960-1969 92 22.6 97 22.5 189 137 23 43 19,7 180Lung 1970 16 3.9 9 2.1 25 20 3,4 1 0,5 21Pleura 1972 36 8.9 31 7.2 67 53 8,9 15 6,9 68Abdomen 1976,1979 10 2.5 5 1.2 15 15 2,5 2 0,9 17Liver 1977 55 13.5 30 6.9 85 68 11,4 13 5,9 81Skin 1982 20 4.9 23 5.3 43 32 5,4 7 3,2 39CNS 1983,1984 13 3.2 3 0.7 16 12 2 2 0,9 14Skeleton 1985 64 15.7 65 15.1 129 95 15,9 35 16,1 130Other 1951,1971,1981,1989 6 1.5 17 3.9 23 17 2,8 7 3,2 24Unknown 0 0 2 0.4 2 1 0,2 1 0,5 2

ER* PR*

*Cut-off value of 0.05 fmol/µg DNA and 10%, for monoclonal antibody based biochemical and IHC/ICC methods, respectively

ER negative ER positive PR negative PR positive


ER status in tumour relapse

Hormonal receptorStatus Number Percent Number PercentER status*Prim(+)/Rel(+) 213 44,65 136 39,42Prim(+)/Rel(-) 123 25,79 105 30,43Prim(-)/Rel(+) 32 6,71 22 6,38Prim(-)/Rel(-) 109 22,85 82 23,77Total number 477 100 345 100

Local and systemic relapse Systemic relapse

*Cut-off value of 0.05 fmol/µg DNA and 10%, for monoclonal antibody based biochemical and IHC/ICC methods, respectively

Documents

Discordance in hormone receptor status in breast cancer during tumour progression Eva Karlsson (1,2) Linda Lindström (1) Ulla Wilking (1) Lambert Skoog