Medical Writer: Stijn van den Borne, MSc.
06 September 2016

Breast Cancer

Ki67 IN BREAST CANCER: FRIEND OR FOE?

Ki67 in breast cancer: friend or foe?

Early April, Huh et al. reported new progress in breast cancer screening (1). Researchers were able to detect proliferation marker Ki67 in non-breast cancer tissue. Low levels in healthy breast tissue correlated with a lesser lifetime chance of breast cancer. Higher levels of Ki67 in normal breast tissue showed increased chance of developing breast cancer. The results were published in Cancer Research.

Another study by Arnedos et al. focussed on the effect of CDK4/6 inhibitor palbociclib on KI67 (2). This research was recently presented at the AACR 2016 meeting in New Orleans. Palbociclib was able to invoke a significant Ki67-level drop.

After a decade of Ki67-controversies, these results put Ki67 back in the spotlight.

Camrelizumab anti-PD-1 with or without chemotherapy for NPC

What is Ki67?

Ki67 is a biomarker for cancer cell proliferation. It is most useful in hormone-sensitive breast cancers (3). Staining for Ki67 by immunohistochemistry (IHC) is relatively straightforward. However, the interpretation is not. Non-standardised testing and inter-laboratory variability have led to controversies around this biomarker. There are several antibodies to stain for Ki67, there is no standardised protocol, and the cut-off values for ki67-high levels have not been established. In practice, 15% positive cells often denote the boundary for ‘Ki67 high’. However, this is an arbitrary limit which was never validated in clinical studies.

Use of Ki67 in Risk of Recurrence Scores

The first use of Ki67 in a recurrence score is the utilisation of the biomarker in the preoperative endocrine prognostic index or PEPI-score. Ellis et al. conducted a study to predict treatment outcome in oestrogen receptor-positive breast cancer (4,5). 228 post-neoadjuvant hormonal therapy tissue samples were analysed. The analysis included post-treatment oestrogen receptor (ER) status, Ki67-level index, histological grade, pathological tumour size, nodal status and treatment response. The study led to the PEPI-score. PEPI can help predict recurrence-free survival (RFS) after neoadjuvant treatment. Ellis et al. validated the PEPI score in the IMPACT trial (5).

More recently, KI67 is utilised by two molecular tests developed to help predict the risk of recurrence in breast cancer. It must be noted that instead of IHC, both these tests are based on reverse transcriptase-polymerase chain reaction (RT-PCR). Therefore, they determine gene expression rather than protein staining.

The first of these molecular tests is OncotypeDX, a 21-gene RT-PCR assay. OncotypeDX can predict the risk of recurrence in patients with ductal carcinoma in-situ (DCIS) (6). It can also be used in invasive oestrogen receptor-positive (ER+) breast cancer (7). Finally, it can be applied in both nodal positive- and negative disease (8).

The second molecular test utilising Ki67 is Prosigna (also: Prediction Analysis of Microarray 50 or PAM50). Prosigna is a 50-gene RT-PCR assay. Ki67 is one of the 50 genes included as a marker of proliferation. Prosigna was validated by Gnant et al. in the ABCSG-8 and TransATAC studies (9,10). The latter trial marked a direct comparison between Prosigna and OncotypeDX. Prosigna can predict the risk of recurrence in post-menopausal women with ER+ early breast cancer.

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The Value of Ki67

Despite the controversies, Ki67 is well documented as a prognostic marker for disease outcome (11). Several studies have correlated high Ki67 levels with higher risk of recurrence.

Furthermore, Ki67 is also a predictive marker. In neo-adjuvant setting, Dowsett et al. have provided an overview of the possible roles for Ki67 (figure 2) (3). Before neo-adjuvant treatment, Ki67 can be used as a marker to select patients who can avoid chemotherapy. During neo-adjuvant treatment, Ki67 can help triage patients not responding to hormonal treatment. Finally, after neo-adjuvant treatment, Ki67 is part of the PEPI score, which can help select patients for adjuvant chemotherapy (5).

Most recent research presented at AACR 2016 shows CDK4/6 inhibition by palbociclib to reduce Ki67 levels (2). This raises questions on the duration of such response. Is the drop in Ki67 permanent? Or is it a transient effect as previously reported in endocrine therapy? Moreover, will the drop in Ki67 result in a significant clinical improvement?

Future

The study in Cancer Research earlier this month suggests an even more novel use of Ki67 (1). Utilising Ki67 on healthy breast tissue to determine breast cancer risk is a new approach. Although the data requires further validation, it is an interesting concept. Unfortunately, many controversies surrounding Ki67 have are yet to be resolved. Staining and interpretation standardisation combined with clinical validation of the Ki67 high value will need to be resolved. Standardisation could tremendously help the Ki67 proliferation biomarker. Nevertheless, it seems to be an important biomarker and one that is here to stay.

References:

Huh SJ et al. Cancer Res. 2016.
Arnedos M et al. Cancer Res. 2016:CT041.
Dowsett M et al. J Natl Cancer Inst. 2011;103:1656-64.
Ellis MJ et al. Cancer Res. 2003;63:6523-31.
Ellis MJ et al. J Natl Cancer Inst. 2008;100:1380-8.
Paik S et al. NEJM. 2004;351:2817-26.
Paik S et al. J Clin Oncol. 2006;24:3726-34.
Mamounas EP et al. ASCO Annual Meeting Proceedings 2012;30(27_suppl):1
Gnant M et al. Ann Oncol. 2014;25:339-45.
Dowsett M et al. J Clin Oncol. 2013;31:2783-90
Yerushalmi R et al. Lancet Oncol. 2010;11:174-83.

Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).

Ki67 IN BREAST CANCER: FRIEND OR FOE?