Abstract 

Early stage breast cancer accounts for approximately 70% of all cases of breast cancer, posing a great treatment dilemma as most oestrogen receptor-positive node-negative patients do not recur. Genomic profiling tools such as Oncotype DX testing has met the need for a tool to aid treatment decision-making, and over the past 10 years, Oncotype recurrence scores have become increasingly utilised in clinical practice. Numerous studies have validated the use of the Oncotype DX genomic profiling tool, however, unfortunately it is not accurate in every case.

Methods

We carried out an observational study in a large tertiary referral centre in Cork University Hospital over a five-year period (October 2010 to December 2015) and identified patients with a recurrence despite a low Oncotype score. 

Results

Over this period, there were 445 Oncotype assays performed, on both node-negative and node-positive breast cancer patients as part of the SWOG trial. A total of 61.83% patients had low Oncotype scores, (< 18), 34% had intermediate scores, and 4.22% had high scores. Three cases were identified where the patient presented with a clinical recurrence despite a low Oncotype score. These three cases are described, and the role of re-biopsying at recurrence is outlined. 

Discussion

This observational study demonstrates the importance of vigilance in clinical follow-up. The role of re-biopsy at relapse in this study was demonstrated to be of critical importance, as biopsy of metastatic lesions significantly changed therapy, and in one case, provided a new diagnosis. These cases demonstrate the limitations of the Oncotype DX score, and we suggest that a registry of patients who do relapse despite a low Oncotype score should be established for further research to allow a prospective analysis of such patients. 

Introduction

Breast cancer is the most frequently diagnosed cancer in Irish women, with approximately 2,700 women newly diagnosed with breast cancer per annum.¹ In the US, approximately 246,600 women are newly diagnosed with breast cancer each year.² Early stage breast cancer accounts for approximately 70% of all cases of breast cancer.¹ This large burden of disease has traditionally posed a great treatment dilemma for clinicians as most oestrogen receptor (ER)-positive node-negative patients do not recur, and only 4% will benefit from the addition of chemotherapy.³

The need for a tool to aid treatment decision-making in this group of patients was met by the arrival of genomic profiling tools, such as Oncotype DX testing; over the past 10 years, Oncotype Recurrence Scores have become increasingly utilised in clinical practice.⁴

Predicting risk of distant recurrence

Numerous studies have validated the use of the Oncotype DX genomic profiling tool. Most recently, the TAILORx study published in 2015 showed that with a recurrence score of 11, with hormonal therapy alone, there is a 7.3% risk of distant recurrence at 10 years (95% CI; 5-10%). With a median follow-up time of 69 months, the five-year distant recurrence free interval with a recurrence score < 11 was 99.3% (95% CI 98.7-99.6%).⁵

The Israel Registry Outcome Study similarly showed that with a low recurrence score, where 99% were treated without chemotherapy, there was a five-year distant recurrence risk of 0.5%.⁶ The SEER Registry found a highly statistically significant relationship between a low recurrence score and breast cancer specific mortality – only 45 events in 21,023 patients with a recurrence score < 18 – and excellent outcomes in patients treated with hormonal therapy alone.⁷

In Ireland, it has been found that Oncotype DX has had a significant impact on adjuvant treatment recommendations, with a 57.7% net reduction in chemotherapy use in node-negative, ER-positive, early stage breast cancer.⁸

The knowledge that a patient will not benefit from adjuvant chemotherapy does not imply that the risk of distant recurrence is non-existent. Oncotype DX offers great expectations to reassure, reduce the need for adjuvant chemotherapy, and identify patients requiring more intensive therapy but, unfortunately it is not accurate in every case. Here, we confront the ‘bleak house’ – those cases that recur despite our great hope and a reassuring Oncotype DX score. 

A single-centre experience: recurrence despite low Oncotype score

We carried out an observational study in a large tertiary referral centre in Cork University Hospital over a five-year period, from October 2010 to December 2015, and identified patients with a recurrence despite a low Oncotype score. Over this period, there were 445 Oncotype assays performed, on both node-negative and node-positive breast cancer patients as part of the SWOG trial. 

A total of 61.83% had low Oncotype scores (< 18), 34% had intermediate scores and 4.22% had high scores. Three cases were identified where the patient presented with a clinical recurrence despite a low Oncotype score. 

Case 1

A 66-year-old lady diagnosed with grade 2 invasive mucinous carcinoma (hormone sensitive, HER2-negative) had an Oncotype recurrence score of 12. She recurred 18 months following completion of radiation therapy, when investigation of atypical chest pain revealed a lung nodule on imaging. 

Case 2

A 58-year-old lady with grade 1 invasive lobular carcinoma (hormone sensitive, HER2-negative) and an Oncotype recurrence score of 13, two years later presented with hip pain, and was found to have bone and liver metastasis on imaging. 

Case 3

A 65-year-old lady with grade 2 invasive ductal carcinoma (hormone sensitive, HER2-negative) had an Oncotype recurrence score of 16. Investigation of vertigo and headaches four years following therapy found brain and pulmonary metastases, suspicious for recurrence of breast carcinoma. 

The role of re-biopsy

All three patients clinically and radiologically had a recurrence of their breast cancer, however in light of increasing understanding regarding inter- and intra-tumour heterogeneity,⁹ especially regarding discordance rates in hormone receptor status in primary and recurrent breast tumours,¹⁰ a decision was made to re-biopsy the metastatic lesions.

Case 1

The lung nodule was biopsied and found to be concordant with the original biopsy specimen. The patient was found to have progressive disease on hormonal therapy, and is now clinically well on chemotherapy.

Case 2

This patient had a biopsy of her liver metastases, which was found to be discordant with her original tumour. The metastatic lesion was found to be HER2-positive, whereas the original lesion was HER2-negative. She was commenced on HER2-targeted therapy, however, unfortunately, developed brain metastases.

Case 3

The patient clinically and radiologically appeared to have metastatic breast carcinoma, however a lung biopsy revealed a BRAF-mutated malignant melanoma. She passed away of causes related to metastatic melanoma.

Conclusion

Although a low Oncotype score predicts a favourable outcome with very low rates of recurrence, some patients will relapse. The rate of relapse in our institution was concordant with outcomes of trial data and registry data. This observational study demonstrates the importance of vigilance in clinical follow up. 

The role of re-biopsy at relapse in this study was demonstrated to be of critical importance, as biopsy of metastatic lesions significantly changed therapy, and in one case, provided a new diagnosis. 

These cases demonstrate the limitations of the Oncotype DX score, and we suggest a registry of patients who do relapse despite a low Oncotype score should be established for further research to allow a prospective analysis of such patients. 

Compliance with ethical standards

Funding

There was no funding for this study.

Conflict of interest

All authors declare that they have no conflict of interest. 

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study, as part of the TAILOR X trial.

References

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