Mahesh Iddawela MBBS,FRACP, PhD (Cantab)

Consultant Medical Oncologist , LaTrobe Regional Hospital

Department of Anatomy & Developmental Biology

Biomedicine Discovery Institute

Monash University

Clayton.

Breast and Prostate Cancer

Management and Survivorship

Breast Cancer Survival

Survival rates are better in Australia

than most other countries in the world

In the last 25 years

the risk of dying

from breast cancer

has fallen by 2%

every year

Incidence has steadied while

mortality continues to fall

Source: Australian Institute of Health and Welfare & National Breast Cancer Centre 2009. Breast cancer in Australia: an overview, 2009.

Early breast cancer

• Breast cancer confined to the breast and

nearby lymph nodes

• Aim of treatment is cure

Secondary breast cancer

(metastatic, advanced, stage 4)

• Cancer that has spread

beyond the breast and

lymph nodes to other

more distant parts of the

body

• Incurable, but ….

• Chronic illness– Some women survive for

many years

Diagnosis and next steps

• Biopsy of abnormal area– confirm if it’s cancer

– May include a biopsy of lymph nodes

• Appointment with a surgeon to discuss– when to remove the tumour

– what surgery is needed for the axillary nodes

• Pathology– report on the tumour

Local treatment: Surgery

• Surgical options– Breast conserving (lumpectomy)

– Mastectomy, with or without reconstruction

Local treatment: Axillary surgery

• Sentinel node biopsy– No signs of lymph node involvement

• Axillary clearance– Known LN involvement

– Following positive SNB

After surgery, the pathology report

tells us…

…about the tumour

•How big is it– Size in mm

•Did the surgery clear it?– Margins

•Has it spread to the lymph nodes?– Number involved

•Is it growing slowly or quickly?– Grade (1,2,3)

…and what is making it grow

•Is it driven by hormones– Oestrogen receptors

– Progesterone receptors

•Is it driven by overactivity of

HER2?– HER2 normal (negative)

– HER2 increased (positive)

•Is something else driving the

growth?– Triple negative

Further treatment decisions take this information, plus a woman’s

age and other medical conditions, into account.

Local Treatment: Radiotherapy

• Usually given to breast area after breast

conserving surgery (lumpectomy)

• May need to be given after mastectomy

Systemic (adjuvant) treatment

Controlling microscopic breast cancer cell growth locally or around the body.

Aim is to increase the chance of overall survival by reducing the risk of recurrence of breast cancer without increasing the risk of significant other illnesses.

Systemic treatments may involve a combination of:• chemotherapy• hormone (endocrine) therapy (e.g. tamoxifen)• targeted therapy (e.g. Herceptin)

Paradigm shift in the way breast cancer is viewed

Hormone blocking therapies

• Tamoxifen– blocks oestrogen receptor cells so that

oestrogen can’t get into the cancer cells

and stimulate their growth

– used in pre and post menopausal women

• Aromatase inhibitors (Arimidex,

Femara, Aromasin)– reduce the amount of oestrogen produced

in the body so it is not able to ‘feed’ cancer

cells

– used in post-menopausal women only

Breast cancer recurrence and

hormone therapy

26.5%

38.3%

15.1%

24.7%

0

10

20

30

40

50

0 5 10 15

Pe

rce

nta

ge

of

wo

me

n w

ho

ex

pe

rie

nce

a r

ecu

rre

nce

Years

Women who did not take hormone therapy

Women who did take hormone therapy for five yearsafter diagnosis

Side effects of hormone therapy

• Hot flushes

• Interference with sleep

• Mood changes

• Joint stiffness

• Joint pain (arthralgia)

• Decreased sex drive

• Vaginal symptoms

• Thinning hair and nails

Can be short and long term

Herceptin reduces recurrence in HER2+

early breast cancer by about half (2006)

87% 85%

Early breast cancer

%

US trials: disease free survival

... and improves survival for women with secondary disease

Triple negative breast cancer

• Around 15% of breast cancers

• Often associated with BRCA1 gene

mutation

• No receptors to target

• Chemotherapy very effective

• Research into new treatments– PARP inhibitors

– Antiangiongenic agents

– Epidermal growth factor receptors (EGFR)

How common or Incidence

6/29/2018 (18)

• Australia - 19400 cases and 3800 deaths

• Victoria - 4500 new cases and 850 deaths

• Gippsland- 258 cases and 57 deaths

6/29/2018 (19)

What to do when first line

Docetaxel treatment fails?

VS.

In 2011 the choices were limited

Palliative Chemotherapy

Phase I study

Beach

Targeting the Androgen Pathway

• Androgen Biosynthesis Inhibitors– *Abiraterone Acetate

– TAK 700

– VN/124-1 (TOK-001)

• Novel Anti-Androgens– *Enzalutamide (MDV3100)

– RD 162

– EPI-001 (AR N-Terminal)

– SNARE-1 (selective nuclear receptor exporter-1)

* FDA approved

De Bono et al. NEJM

2011

14.8 vs. 10.9 <0.05

COU-AA- 301 Study Abiraterone vs.placebo

AFFIRM study

• 18.4 vs. 13.6 months

months

13.6

• Scher et al. NEJM

2012

23ASCO June 2012

Early Chemotherapy in Metastatic

Prostate cancer

• CHAARTED and STAMEDE showed a

benefit to early chemotherapy.

• This has changed the management of

prostate cancer.

• Work being done to understand the role of

subgroups in the studies.

Sweeney et al, NEJM 2015

57 vs 44 months

13 months

OS Benefit in Recent CRPC Trials

Trial/Agent

Mechanism ComparatorSurvival

(months)Hazard Ratio

P-value

AFFIRMEnzalutamide

2012

Androgen Receptor Signaling Inhibitor

Placebo 18.4 vs. 13.6 0.631 <0.0001

COU-AA-301 Abiraterone +

prednisone 2011

CYP17 InhibitorPlacebo +prednisone

14.8 vs. 10.9 0.646 <0.0001

TROPIC Cabazitaxel +

prednisone2010

CytotoxicMitoxantrone +

prednisone15.1 vs. 12.7 0.70 <0.0001

Alpharadin*2012

Alpha-particle emitting

radionuclidePlacebo 14.9 vs. 11.3 0.69 0.0018

* Only 60% of these patients were post-docetaxel patients

De Bono et al. ASCO 2012

Blood tests and outcome in prostate cancer- Trial

lead by Gippsland Oncology

• Patients treated with chemotherapy or hormonal

therapy get blood tests to evaluate circulatory DNA

and mRNA.

• Outcome correlated with the response to treatment.

• Thus far 35 patients have been recruited.

• Collaboration between Prostate Cancer Research

Group at Monash, Latrobe Regional Hospital,

Eastern Health, Charles Gardner and Edith Cowan

University.

PI- Mahesh Iddawela

Response to treatment and AR copy /ARV-7 status

• 2 out of 3 patients had poor response to hormonal therapy, if both AR and ARV-7 are altered.

• AR gained but ARV-7 negative samples had a better response to AR targeting (> 50% PSA decline).

• Some patients are genomically neutral with no AR/ARV-7 changes.-100

-80

-60

-40

-20

0

20

40

60

80

100

120

LRH03 LRH04 LRH05 LRH08 LRH09 LRH10 LRH11

% P

SA

resp

on

se

Waterfall plot of PSA Response

Red- both AR and ARV-7 altered

Blue- AR gain, AR normal and no ARV-7

• Long-term

- Cardiovascular Risks

- Increasing weight

- Diabetes

- Osteoporosis

- Psycological issues

6/29/2018 (29)

Gippsland Cancer Survivorship Program

Eli Ristevski, Taryn Robinson, Jeannette Douglas, Danielle Roscoe, Michelle Pryce, Trisha Wright

Mahesh Iddawela

Gippsland Cancer Care CentreLatrobe Regional Hospital

In collaboration with:

Challenges of Cancer Survivorship

• Survivors are at risk for a wide range of late

physical effects of their primary treatment

• Compared with others, cancer survivors have a

substantially increased burden of illness:

– Days lost from work, inability to work

– General health perception

– Need help with daily activities

Ganz PA. J Clin Oncol. 2006;24:5105-5111. American Society of Clinical Oncology. Cancer Advances Information

From the Experts: Cancer Survivorship – Increasing Survival, Improving Lives. December 2004.

Participants

Cancer survivors

- 18 years

- low risk

Carers

- Self identify as carer

Clinicians & Services

- Oncology specialists &

Nurses

- GPs

- Service Managers

Breast

Prostate

Colon

Lymphoma

Oncological Emergencies

• Complications of the cancer (treatment)

Spinal cord compression – cancers which spread to bone (BLKTP), myeloma, primary bone tumours (Ewings, osteosarcoma), bone lymphoma

Superior vena caval obstruction – SVCO –mediastinal tumours (lung cancer, lymphomas, germ cell tumours, thyroid, lung cancer)

Oncological Emergencies

Complications of the cancer (treatment)

Hypercalcaemia – BLKTP, myeloma, paraneoplastic –lung cancer

Acute renal failure – ureteric obstruction (gynae masses), prostatic obstruction (prostate cancer, sarcoma), n.sepsis, hypercalcaemia, myeloma

Intestinal perforation – ovarian cancer, bowel cancer,

+ avastin

Oncological Emergencies

Complications of treatment (cancer)

neutropenic sepsis (chemotherapy)bowel perforation (chemotherapy, avastin)bleeding / thrombosis (chemotherapy,

avastin)congestive heart failure (anthracyclines,

Herceptin, sunitinib)acute renal failure (high dose methotrexate,

neutropenic sepsis, platinum, ifosfamide)

Overview

1. Neutropenic sepsis

2. Spinal cord compression

3. Hypercalcaemia

Neutropenic sepsis

• Kills !!!!

• Rate of death 1% of among adjuvant breast cancer patients.

• Can be avoidable

• National agenda Sepsis management to reduce deaths.

• Treatment within 1 HOUR

Neutropenic sepsis

Definition• Fever > 38.5° or 38 ° 1hr apartwithNeutrophil<1.0 or predicted to decrease

-Unwell with no temperature-Patients on corticosteroids-Hypotension/Hypothermia

• Gram negative cover important- severe infections-infections in sites outside blood (urine, biliary, skin and

respiratory)

• Anaerobes unlikely (3.4%)-mucositis, diarrhoea, necrotising neutropenic colitis

Spinal cord compression

• Risk cord compression in the five years before death was 2.5% (0.2-7.9%)1.

• Autopsy studies suggested that 5 percent of patients dying with cancer have SCC.

• Vertebral metastasis at autopsy in 90% of prostate, 74% of breast and 45% of lung.

1Clin Oncol (R Coll Radiol) 2003 Jun;15(4):211-7

Epidemiology

Patients with known malignancy

Common malignancies1-

Prostate (19%), non-small cell lung (18%)

and breast (15%), Kidney (10%)

Others- NHL, plasmacytoma, MM.

Patients with unknown malignancy

Lung cancer, CUP, MM, NHL make up 78%

Acta Neurochir (Wien) 1990;107(1-2):37-43.

Pathophysiology

Thecal sac compression

and 85-90% due metastatic

tumour in the vertebral

bodies.

10% due to paraspinal

mass (esp. lymphoma)

Encircle thecal sac

vasogenic oedema

& infarction

•

Diagnosis

• Clinical features• Early recognition of features is essential for best

management.• Pain (83-95%)-preceeds neurology 7 wks.

-lumbosacral-radicular-thoracic-bandlike

• Motor (60-85%) -weakness pyramidal-cauda equina-weakness and reduced deep reflexes-increasing weakness and gait problems

Sensory (less common)-ascending numbness

-sensory level 1-5 dermatomes below compression.

Bladder/bowel dysfunction- late finding.

-autonomic neuropathy with retention can be sole

symptom

Ataxia- in cancer patients raise suspicion.

Investigations

• MRI –WHOLE SPINE-21% cases missed if only thoracic or lumbosacral imaged.

• CT Myelography- if MRI CI

D.Dx

• SCC

• Malignant disease-vertebral metastasis only-Leptomeningeal metastasis (coexist with headache, cranial nerve

palsies)-malignant plexopathy- involving any of the peripheral nerve plexus.

-radicular pain-Brachial-lung, breast

-Radiation myelopathy- past radiation, 12-15 months,UMN and numbness

Management

• Dexamethasone 8mg BD.-improve the pain and neurology

• PPI• Thromboprophylaxis• Laxatives• Consider neurosurgery

-solitary lesion-good performance status-stage of systemic disease