Cancer Genomics - Genomics in predicting prognosis of cancer - Week 10

Question 1

Genomics can be used to

Answer 1

predict prognosis of cancer

Question 2

Breast cancer is the

Answer 2

third most common cause of UK cancer-related deaths.

Question 3

Breast cancer survival depends on a number of factors including

Answer 3

stage of disease, tumour biology and treatment.

Question 4

Breast cancer survival - early diagnosis

Answer 4

More than 90% of women diagnosed with early breast cancer survive for at least 5 years, and 78% survive for 10 years.

Question 5

Breast cancer survival - late diagnosis

Answer 5

In contrast, only 13% of those diagnosed with advanced disease survive for more than 5 years. In this talk we will be focusing on early breast cancer.

Question 6

Treatment for early stage breast cancer usually involves

Answer 6

surgery followed by adjuvant therapy of radiotherapy, chemotherapy, hormone therapy, biological therapy or a combination of these.

Question 7

The side effects of these adjuvant therapies, particularly

Answer 7

chemotherapy can be particularly unpleasant so it is important to only give it to those patients that need it.

Question 8

The decision whether to give adjuvant therapy is based on

Answer 8

clinical history, stage and grade of the disease, the likely course of the disease, molecular characteristics of the tumour and the patients preferences.

Question 9

what is PREDICT?

Answer 9

online prognostic and treatment benefit calculator, is the most widely used tool in the NHS in England to calculate risk of recurrence in patients who have had early breast cancer.

Question 10

the PREDICT tool looks at

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size and type of the cancer at diagnosis, whether the cancer has spread to involve lymph nodes, and whether or not the cancer expresses markers such as the oestrogen receptor (ER), HER2 and KI67 to predict average survival and how much benefit might be gained on average from different treatment options (shown in the bottom picture).

Question 11

PREDICT and other such computer algorithms produce

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good estimates of survival and recurrence, but they cannot say whether an individual patient will survive their cancer or not.

Question 12

Limitation of PREDICT

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It can only provide the average survival rate for people in the past of a similar age and with similar cancers so do have limitations.

Question 13

For this reason a number of tumour profiling tests have been developed that look at

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the activity of a range of genes in tumour sample to help decision making about whether adjuvant chemotherapies required to ensure patients are not being under or over treated.

Question 14

Examples of some of the profiling tests:

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EndoPRedict (Myriad Genetics)

MammaPrint (Agendia)

Oncotype DX Breast recurrence Score (genomic Health)

Prosigna (NanoString Technologies)

IHC4 and IHC4+C

Question 15

EndoPRedict (Myriad Genetics)

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Measure the expression of 12 genes: 3 proliferation-associated genes, 5 hormone recetpro-associated genes, 3 reference (normalisation) genes and 1 control gene

Question 16

MammaPrint (Agendia)

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Measure the expression of 70 genes, including genes associated with 7 different parts of the metastatic pathway: growth and proliferation, angiogenesis, local invasion, entering the circulation, survival in the circulation, entering organs from the circulation, and adaption to the micronevionrment at a secondary site

Question 17

Oncotype DX Breast recurrence Score (genomic Health)

Answer 17

Oncotype DX quantities the expression of 21 genes: 16 cancer-related genes correlated with distant recurrence-free survival, and 5 reference (normalisation) genes

Question 18

Prosigna (NanoString Technologies)

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Prosigna measures the expression of 50 genes used for intrinsic subtype classification, 8 housekeeping genes used for signal normalisation, 6 positive controls and 8 negative controls

Question 19

IHC4 and IHC4+C

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The 4 immunocytochemistry tests are: ER, progesterone receptor (PR), HER2 and the proliferation marker KI67.

Question 20

Oncotype DX in detail

Answer 20

• Expression of 21 genes by RT-qPCR
o 16 cancer related genes
o 5 reference genes

The results are presented as a quantitative score, based on a continuous scale from 0-100. The score reflects individual tumour biology—the higher the score, the higher the risk of distant recurrence and the higher the likelihood of chemotherapy benefit are for that patient. So the score Reveals underlying tumour biology and Guides treatment decisions

Question 21

Until 2018 Oncotype DX

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has been extensively evaluated by multiple studies looking at the low, intermediate and high risk scores, however in July 2018 it was shown that the OncotypeDX assay could categorically differentiate between the those women early stage breast cancer who will receive no benefit from chemotherapy, is 70% and those women early stage breast cancer that will befit (30%)….
Loosing the intermediate risk scores. this was shown by the TailorX study

Question 22

TailorX study =

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This landmark study which was largest, independently-led, randomized adjuvant breast cancer treatment prospective trial that involved 10,273 women.

Question 23

This TailorX trial summarised

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low and high risk on OncotypeDX scores as shown on this slide so patients with a score of 0-25 show excellent outcomes when treated with endocrine therapy alone wile those with a score of more than 25 were shown to have significant benefit from chemotherapy

Question 24

The TailorX study also showed that clinical risk features alone

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are not sufficient to determine chemotherapy benefit with 25% of patients with a low recurrence score having a high clinical risk and would have been over treated and 43% of patients with a high recurrence score had a low clinical risk meaning they would have been undertreated.

Question 25

NICE used this TailorX study along with

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9 other when revaluating the evidence for tumour profiling technologies after removing their endorsement of OncotypeDX in January 2018

Question 26

In December 2018, NICE published new guidance on all the

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assays previously mentioned recommending Oncotype DX and Endopredict as technologies that could be used for people with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative and lymph node (LN)-negative early breast cancer, but only IF they have an intermediate risk of distant recurrence using a validated tool such as PREDICT or the Nottingham Prognostic Index and information provided by the test would help them choose, with their clinician, whether or not to have adjuvant chemotherapy

Question 27

Which techniques are not recommended to use?

Answer 27

Mammaprint and IHC4 assays are not recommended for use.

Question 28

These recommendations are were based the evaluation of many studies

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– 153 references were included in the NICE review of the technologies including the TailorX study

Question 29

Take home message - genomic profiling

Answer 29

Genomic profiling can be used to predict prognosis of cancer

Question 30

Take home message - breast cancer detection

Answer 30

Early breast cancer and the OncotypeDX test is a good example, identifying those patients who will benefit from chemotherapy

Question 31

Take home message - tests

Answer 31

Tests that are available are continually being assessed and improved

Question 32

Take home message - new tests

Answer 32

New tests continually being developed