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10th April 2019Room 2004, TRI, Princess Alexandra Hospital,

Woolloongabba, QLD

Queensland Molecular Tumour Board

Patient 46 yr. old femaleSelf-detected L breast mass

MMG/US March 2017: 40mm lesion mediallyCore Box: invasive Ca

Medical History• Chronic R breast abscess, surgically excised• Obesity• Asthma• HTN• Previous IVDU. On methadone program

Family History

• Not in contact with mother, but thinks she has had breast & ?ovarian ca• Maternal aunt RIP breast cancer age ~30 years

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Staging scans: Nonspecific 7mm LUL nodule.

WLE/SLNBx 18/07/17:

68mm, Gr 3 invasive ca, NST.ER + (60%), PR + (60%), HER2 non-amplified.Node negative.Positive margins, so underwent completion mastectomy.

Repeat CT staging Aug 2017 Increase in LUL nodule: pulmonary metastases.

Systemic therapy:Commenced ribociclib/letrozole/zoladex Aug 2017Continues on therapy

Molecular profile (re-analysis) 15/3/19

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RSF1 expansion (diagnostic)Predicts lack of response to adjuvant tamoxifen, (n=672 but mutation is rare n=46) interaction( HR = 1.11 p = 0.09) Keilty et. al. PLoS One. 2013; 8(12): e81740.

TP53 Mutation: (diagnostic)Berns et. al. Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer. (n=202) Cancer Res. 2000 Apr 15;60(8):2155-62.

• TP53 loss a predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.0014)

• 66% of TP53- responded to tamoxifen, 31% of the patients TP53+ mutation responded to tamoxifen therapy

• Results only seen in ER+ patients• Response to Rad

TP53 cont. Berns et. al Figure 1: (right)

PFS (left) and survival after the start of tamoxifen treatment (right)

• TP53 gene status in all patients (ALL),

• high ER (>75 fmol/mg protein; ER-high),

• intermediate ER (10 > ER <75 fmol/mg protein; ER-medium),

• low ER (<10 fmol/mg protein; ER-low).

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CCNE1 expansion (diagnostic): Preclinical data only may infer CDK4/6 inhibitor resistance (not on clinical repost)Herrera-Abreu MT et.al Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer. Cancer Res. 2016 Apr 15;76(8):2301-13.

“CDK4/6 inhibition resistance resulted from bypass of cyclin D1-CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss”

Did find addition information:Diagnostic for Poor P=0.001 Outcome (n=395)Ketomararsi N et. al. Engl J Med 2002; 347:1566-1575 (see figure right)

Similar findings in Ovarian Cancers

• BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to Trastuzumab and chemotherapy in HER2+ (n=549)

• PIK3CA in 30% of samples (HR, 0.67; 95% CI, 0.45 to 1.00)

• Patients without these molecular alterations showed essentially minimal PFS benefit from everolimus over placebo,

PIK3CA mutation

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• PIK3CANCT03337724 - A Study of Ipatasertib in Combination With Paclitaxel as a Treatment for Participants With PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor-Positive, HER2-Negative Breast Cancer

NCT02506556 - Phosphatidylinositol 3-kinase (PI3K) Alpha inhibition In Advanced Breast Cancer

• FGFR1NCT02052778 - A Study of TAS-120 in Patients With Advanced Solid Tumors (NSW and VIC)

Phase 1 dose-escalation, dose-expansion, and Phase 2 study targeting tumors with FGF/FGFR aberrations. The purpose of the study is to evaluate the safety, tolerability, PK, pharmacodynamic, and anti-tumor activity of TAS-120 in patients with advanced solid tumors with and without FGF/FGFR-related abnormalities

Summary

• Mutations related to resistance to tamoxifen.

• CCNE1 (preclinical CDK4/6 resistance and poor outcome)

• FGFR1 expansion early trials only

• PIK3CA activating mutation

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Breast Cancer Case Dr Poh See Choo

Sept 2017

49 year old Caucasian female presented in late 2017 with a history of uncharacteristically “blunt” comments at work. Friends recall her having “no filter” but patient having no recollection of these comments.

Driving deteriorated -> evaluation by optometrist - significant bilateral vision loss, L quadrananopia. Optometrist queried the possibility of aneurysms and after consultation with Mater Eye Clinic Reg -> Recommend urgent assessment at ED for CT scan.

CT brain revealed multiple cystic lesions consistent with brain metastasis.

Clinically no obvious primary

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Investigations

Bilateral mammogram- no abnormality detected

Bilateral Ultrasound of the breast detected 3cm mass in the axillary

tail and 1cm intramammary lymph node.

Core biopsy of the primary breast lesion confirmed Grade 3 invasive

carcinoma which is ER+ve/PR+ve/HER2-ve. Fine needle biopsy of

the lymph node confirmed metastatic disease.

PET/CT scan confirmed brain metastasis only.

Brain MRI showed 4 large tumours – with surrounding oedema

• 2 in R occipito-temporal and 1 in L temporo-occipital area

• 1 in the L cerebellum, close to midline - ataxia

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TREATMENT

Received 35-40Gy stereotactic radiotherapy in 10 # .Started on high dose Dexamtheasone to reduce oedema and prevent hydrocephalus

Endocrine therapy with Letrozole

Plan for 3 monthly scans-> responding to treatment on follow up scans

• Nov 2017 CT and Dec 2017 MRI brain• Jan 2018 and Apr 2018 MRI- brain ongoing response• CT scan- responding to treatment

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April 2018

PET/CT scan and MRI revealed Liver and bony (scapula) mets

-> Fluorouracil, Epirubicin and Cyclophosphamide (FEC100-6 cycles every 3 weeks).

Samples sent for molecular profiling

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Summary of Molecular Findings – Paul Leo

PIK3CA NP_006209.2:p.Asn345Phe

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• BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to trastuzumab and chemotherapy in HER2+ (n=549)

• PIK3CA in 30% of samples (HR, 0.67; 95% CI, 0.45 to 1.00)• PTEN loss in 12% (HR, 0.54; 95% CI, 0.31 to 0.96) • PIK3CA and PTEN 3%

• Patients without these molecular alterations showed essentially minimal PFS benefit from everolimus over placebo,

Clinical Trials targeting PICK3CA

Brisbane

NSW-Peter Mac

NSW & VIS Exclude:Prior treatment with exemestaneBrain Mets

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Trials for high TMB

• Trails for TNBC

• Solid tumors with High Tumor Mutational Burden (TMB-H)

Excelmetastatic

August 2018

PET/CT scan - no evidence of tumour in axilla or breast.

Liver lesion had reduced but still very active.

Based on PIK3CA mutation -aromatase inhibitor and Everolimus

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Dec 2018

PET and MRI - remission – FDG showed inactivity in all sites

-> Continued on AI and Everolimus

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March 2019

PET and MRI - liver met active again and a new lymph node adjacent to liver

Discontinued AI and Everolimus and commenced on Abraxane (Nab-Paclitaxel) for 3 months

Will evaluate response after 3 months and decide whether to resume Everolimus

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Family history

16 years

d 72 yearsAlzheimers 60 years

d 67 yearsETOH

d 26 yearsPostnatal pulmonary Embolism

Germany (Ashkenazi Jewish) England/Scotland/Ireland

59 yrs 57 yrs 55 yrs

n

80 yrs

Positive family history of ca breast

46 yrs Dg Ca Breast 38 yrs

75 yrsDg Ca prostate 70 yrs

n

Dg Ca Breast 80

A+W

96 years75 yearsCongestive heart failure

Nov 2017 BRCA1/2 neg

CHEK2 pos

Ca Breast

March 2019 Consented to research protocol to determine CHEK2 status