A Study to Measure the Expression of the HER2-HER3 Dimer in Tumour and Blood (Exosomes) Samples From Patients With HER2 Positive Breast Cancer Receiving HER2 Targeted Therapies

HERdi PREDICT: A Pilot Study to Measure the Expression of the HER2-HER3 Dimer in Samples From Patients With HER2 Positive Breast Cancer Receiving HER2 Targeted Therapies

The treatment of breast cancer is determined by its 'receptor (or signal) status'. Receptors are signals present on all cells and if abnormal can drive cancer growth. One of the signals that can drive breast cancer growth is the HER2 receptor/signal. One quarter of all breast cancers are found to have too many HER2 signals i.e. HER2-positive breast cancer.

HER2 is a member of the HER-family which constitutes HER1,HER2,HER3,and HER4 signals. Currently, tests can identify breast cancers with too much HER2, from a biopsy, so a cancer doctor can prescribe anti-HER2 treatment to block these signals. These drugs have improved survival rates in HER2-positive breast cancer. Members of the HER family can also 'pair' with each other to activate signals that encourage cancer growth. For example, HER3 naturally 'pairs' with HER2. Though anti-cancer drugs have been developed to target this pairing, the current method of patient selection is not developed to detect pairing of signals in tissue biopsies. A specialist imaging technique called FLIM-FRET (FLIM- Fluorescence Lifetime Imaging Microscopy; FRET- Forster resonance energy transfer) can identify signal pairing on cancer cells from tissue, and potentially, from blood samples.

This study involves having blood tests while participants receive anti-HER2 treatment. The investigators will also seek permission to take samples of cancer tissue from the biopsies that were already carried out, e.g. at diagnosis. Some participants may need an additional biopsy, which will be discussed with participants prior to consent. This study will use the specialist FLIM-FRET technique to measure the signal pairing in tumour samples and blood samples. Investigators will measure if the levels of signal pairing from blood are the same as that from tissue, which could lead to bloods tests being used to select patients for anti-HER2 treatments, instead of invasive tissue biopsies. Changes in signal pairing may also help to predict if a cancer is becoming resistant to treatment.

The study will recruit 40 participants to two groups as outlined below:

Group 1: Early HER2 positive breast cancer (20 patients) Group 2: Metastatic HER2 positive breast cancer (20 patients)

The two groups represent the natural spectrum of breast cancer in its clinical presentation.

GROUP 1: EARLY BREAST CANCER

Group 1 will include patients with early HER2 positive breast cancer recommended to receive neo-adjuvant chemotherapy inclusive of HER2 directed therapy (trastuzumab + pertuzumab), prior to proceeding to curative surgery. All participants are expected to have had a diagnostic core biopsy and definitive breast surgery on completion of neoadjuvant chemotherapy as standard of care. Blood samples will be obtained for biomarker analysis in exosomes. Participants in Group 1 A will be requested to have a biopsy on completion of anthracycline based chemotherapy and prior to commencing on HER2-directed therapy.

Group 1 A: Participants in Group 1 commencing treatment with anthracycline based chemotherapy for up to 4 cycles followed by a switch in treatment to taxane based chemotherapy in combination with HER2 directed therapy (trastuzumab + pertuzumab) for up to 4 cycles

Group 1 B: Participants in Group 1 commencing treatment with taxane based systemic therapy in combination with HER2 directed therapy (trastuzumab + pertuzumab) for up to 6 cycles:

GROUP 2: METASTATIC BREAST CANCER:

Group 2 will include patients will include participants recommended commencing any line of palliative systemic therapy inclusive of a HER2 directed therapy by their treating oncologist. All participants are expected to have had a diagnostic core biopsy. Blood samples will be obtained for biomarker analysis in exosomes.

Inclusion Criteria:

1. Female or Male aged 18 years or above.

2. Histologically documented breast cancer. In participants with metastatic breast cancer (Group 2), the biopsy should have been obtained following or at the time of diagnosis of metastatic breast cancer. (refer to inclusion criteria 10 for group 2 specific criteria)

3. HER2 positive breast cancer, to be established by immunohistochemistry and confirmed by fluorescence in situ hybridisation or dual in situ hybridisation in borderline cases as per standard of care guidelines.

4. Confirmation of availability of sufficient tumour tissue (from diagnostic core biopsy) for biomarker analysis (Refer to study laboratory manual)

5. Fit for treatment with chemotherapy in combination with HER2 targeted therapy as per investigator discretion

6. Life expectancy of 12 weeks or more.

7. Participant is willing and able to give informed consent for participation in the study and in the investigator's opinion, is able and willing to comply with all study requirements.

8. Participant willing to undergo additional biopsies when required i.e. Group 1A and Group 2

9. Willing to allow his or her general practitioner to be notified of participation in the study [optional].

10. Group 2 specific criteria

    1. The pre-treatment tumour sample for biomarker analysis in group 2 will be acquired from the diagnostic biopsy acquired when participants were first diagnosed with metastatic HER2 positive breast cancer. The biopsy should have been acquired following or at the time of the diagnosis of metastatic breast cancer (i.e. cannot use tumour tissue acquired during a prior diagnosis of early/locally advanced breast cancer for this study's biomarker analysis). The biopsy may be acquired from a breast mass or a metastatic site. If a biopsy following or at the time of the diagnosis of metastatic breast cancer has not been carried out, a study specific biopsy will need to be organised.
    2. Only patients recommended first line treatment with a taxane, trastuzumab and pertuzumab by their physician, are eligible. Potential participants being considered for treatment with any other treatment combinations with HER2 targeted therapies will not be considered eligible.

Exclusion Criteria

1. Significant thrombocytopaenia or abnormal clotting screen or any other condition that would contraindicate a tissue biopsy if this were required, in the investigator's opinion.
2. Participant unwilling to undergo study required tissue biopsies and blood sampling.
3. Any other significant underlying condition or comorbidity which, in the opinion of the investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study or the participant's ability to participate in the study.
4. Inability of participant to co-operate with study procedures as judged by the investigator.