case4 breastcancer handout

8/18/2019 Case4 BreastCancer Handout

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014 Centre for Cancer Education

Solid Organ MalignancyBreast cancer

Dr Graham DarkSenior Lecturer in Medical [email protected]

Approach to all cases

What is the diagnosis

Why did it happen

What complications are present (disease / treatment)

Introduction

Breast cancer is the most frequent cancer in women after non-melanotic skin tumours (32% of female malignancies)

Causes approximately 13,000 deaths per year in the UK(2002)

The lifetime risk of breast cancer is 1 in 9 women

In England (2001) 80% of patients are alive and disease-freeat 5 years from diagnosis

With improved awareness on the part of both women andhealth-care providers, more breast cancers are beingdiagnosed while still in-situ

UK Cancer incidence and mortality

Breast cancer: Rising incidence Epidemiology of breast cancer

In the UK, the incidence of breast cancer is approximately42,000 cases per year

It is the commonest cause of death in women aged 35 – 54years in England

Follows an unpredictable course with metastases presentingup to 20 years after the initial diagnosis

In England and W ales the 5-year age-standardized survivalrate in 1990 was 62% compared to over 70% in France, Italyand Switzerland. This has improved recently with earlierdetection by screening and improved treatment

Female to male ratio is approximately 100:1


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Epidemiology of breast cancer

RaceWhite women have a higher overall rate of breast cancer than Afri can-

American women; however, this is not apparent until age 40 and ismarked only after menopause

Breast cancer risk is extremely low in Native American women

Geography5-fold variation in incidence among different countries, being lower inJapan, Thailand, Nigeria, and India than in Denmark, the Netherlands,New Zealand, Switzerland, UK & US

Socioeconomic statusincidence of breast cancer is greater in women of higher socioeconomicbackground

Disease siteleft breast is more common than the right

most common locations o f the disease are the upper outer quadrant andretroareolar region

Reasons for fewer breast cancer deaths

Earlier diagnosis

One stop clinics

Screening

Better treatment

More women are cured

More cure saves money on subsequent treatments

Those who aren’t cured are living for longer

More treatments available

Sequential benefits

Breast cancer: Risk factors

Age

Family history / personal history

Previous benign breast disease

Reproductive and menstrual history

Early menarche / Late menopause

Nulliparous / late first pregnancy (>35 years)

Oestrogen therapy

OCP

HRT (relative risk 1.66 in long term users)

RadiationObesity

Alcohol

Risk of developing breast cancer

By age 30...1 out of 2,525

By age 40...1 out of 217





Familial breast cancer

Hereditary predisposition is implicated in around 10% ofbreast cancer cases

Multiple affected relativesYoung age at diagnosis

Multiple primary cancers

Male breast cancers

Ovarian cancer

Autosomal dominant pattern of inheritance

Family history of breast cancer

The overall relative risk of breast cancer in a woman witha positive family history in a first-degree relative (mother,daughter, or sister) is 1.7

Premenopausal onset of the disease in a first-degreerelative is associated with a three-fold increase in risk

Postmenopausal diagnosis increases relative ri sk by only1.5

If first-degree relative has bilateral disease: 5-fold riskincrease

If first-degree relative has bilateral disease prior tomenopause: 9-fold risk increase


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Breast cancer genes

BRCA1

BRCA2

p53 (Li-Fraumeni syndrone)

Others

Cowden syndrome (breast & GI cancers, thyroid disease)

Ataxia telangiectasia

Peutz-Jeghers syndrome

Characteristics of BRCA associated cancer

Younger age of onset

Frequent bilateral occurrence

Worse histological features:

more aneuploidy

higher grade

higher proliferation indices

higher proportion hormone receptor negative

Presenting symptoms

Mammographic findings: discovered in asymptomatic patientsthrough the use of screen ing mammography

Breast lump: the most common presenting complaint. Theincidence can range from 65-76% of patients

Paget’s disease: associated with intraductal carcinomainvolving the terminal ducts of the breast and may have anassociated invasive component. Presents as an eczematoidchange in the nipple, a breast mass, or bloody nippledischarge

Other local symptoms

Breast pain 5%

Breast enlargement 1%Skin or nipple retraction 5%

Nipple discharge 2%, nipple crusting or erosion 1%

Clinical signs

Neck and axilla: lymphadenopathy

Nipple: discharge or retraction

Breast: discolouration, oedema, peau d’orange,erythema, nodules, ulceration, lack of symmetry, skinthickening

Chest: signs of consolidation, nodules in skin

Abdomen: hepatomegaly

MS: focal tenderness in axial and peripheral skeleton

Distant metastases:bone 70%, lung 60%, liver 55%, pleura 40%, adrenals 35%, skin30%, brain 10 –20%

Paget’s disease of the breast

• Erythematous keratotic patchesover the areola area

• Extramammary Paget’s isassociated with internalmalignancy in 50% cases


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Breast self-examination

Recommendation to begin monthly breast self-examination atthe age of 20

Meta-analysis of 12 studies involving a total of 8,118 patientswith breast cancer correlated the performance of breast self-

examination with tumour size and regional lymph node statusWomen who performed breast self-examination were morelikely to have smaller tumours and less likely to have axillarynode metastases than those who did not

A major problem with breast self-examination as a screeningtechnique is that it is rarely performed well. Only 2-3% ofwomen do an ideal examination a year after instruction hasbeen provided

Evaluation of a cystic mass

Fine-needle aspiration (FNA)If the mass is a cyst it can simply be aspirated with a fineneedle, which should yield non-bloody fluid and result incomplete resolution of the lesion

UltrasonographyUsed to determine whether a lesion is solid or cystic, andwhether a cyst is simple or complex

Biopsy A biopsy is indicated if the cyst fluid is bloody, the lesion doesnot resolve completely after aspiration, or the cyst recurs afterrepeated aspirations

Cystic carcinoma accounts for < 1% of all breast cancers An intraluminal solid mass is a concerning sign suggesting(intra) cystic carcinoma, and should be biopsied

Evaluation of a solid mass

The decision to observe a patient with a breast mass thatappears to be benign should be made only after carefulclinical, radiological, and cy tological examinations

MammographyTo assess radiological characteristics of the mass andevaluation of the remainder of the ips ilateral breast as well asthe contralateral breast

FNASimple method for obtaining material for cytologicalexamination. False-positive results from 0%-2.5% and false-negatives varies from 3-27%

Biopsy A core biopsy (18 gauge or larger needle biopsy) can be

advantageous since architectural as well as cellularcharacterist ics can be evaluated. An excisional biopsy , inwhich the entire breast mass is removed, definitivelyestablishes the diagnosis

Evaluation of a non-palpable mass

Wire excision biopsy

Stereotactic-guided core biopsies

Ultrasound-guided core biopsies

Breast MRI

Tumour marker: CA 15.3

Elevated serum levels found in 12.5% of women with benign breastdisease, preoperatively in 11% of women with operable breastcancer, and in 64% of women with metastatic breast cancer

Has no value in screening because of low sensitivity for the earlystages of disease

False positive: Elevated in gynaecological cancers

CA 15.3 elevation increases with increasing stage of disease andhighest levels are seen in patients with liver or bone metastases

It is not accurate enough to be used alone to define response

Several trials have shown that a rising CA 15.3 level during follow-upcan detect relapse 2-9 months before clinical signs or symptomsdevelop

Rising levels indicated recurrence in 73% of those with a recurrenceand in 6% of those without a recurrence

Pathology

Invasive ductal carcinoma

With or without ductal carcinoma in situ is the commonesthistology accounting for 70%

Invasive lobular carcinoma

Accounts for most of the remaining cases

Ductal carcinoma in situ (DCIS)

20% of screen-detected breast cancers. It is multifocal in one -third of women and has a high risk of becoming invasive (10%at 5 years following excision only). Pure DCIS does not causelymph node metastases, although these are found in 2% ofcases where nodes are examined, owing to undetectedinvasive cancer

Lobular carcinoma in situ (LCIS)

A predisposing risk factor for developing cancer in either breast(7% at 10 years)


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Breast cancer: Triple assessment

Clinical examination

Breast imaging

Mammography

Ultrasound

MRI

Fine needle aspiration

Needle core biopsy

Mammotome (vacuum assisted biopsy)

Cytological assessment

Reported asC1-5

1: no cells

2: insufficient

3: normal

4: suspicious

5: malignant

Predictive value of investigations

Modality Imaging 2 3 4 5

Cytology Risk ofCancer %

7.3 22.5 69.3 95.1

0 or 1 13.6 2.3 8.0 40.3 85.2

2 5.3 0.8 3.0 19.4 67.3

3 11.6 1.9 6.8 36.0 82.8

4 83.5 43.2 73.6 95.6 99.5

5 99.2 94.8 98.5 99.8 100

Disposable cutting needle


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No staining is observed ormembrane staining is observed inless than 10% of the tumour cells

Faint membrane staining is detectedin more than 10% of tumour cells.The cells are only stained in part oftheir membrane

Weak to moderate completemembrane staining is observed inmore than 10% of the tumour cells

Moderate to strong completemembrane staining is observed inmore than 10% of the tumour cells

O Negative

1+ Negative

2+ Weak

Positive

3+

StrongPositive

HercepTest staining guide FISH for HER-2

Normal gene copynumber

Amplified gene copynumber

Radioisotope bone scan Bone metastasis

Most of the people who die of cancer each year havetumour metastasis

Bone is the third most common organ involved bymetastasis, behind lung and liver

In breast cancer, bone is the second most common site ofmetastatic spread, and 90% of patients dying of breastcancer have bone metastasis

Breast and prostate cancers metastasise to bone mostfrequently, which reflects the high incidence of both ofthese tumours, as well as their prolonged clinical courses

Other tumours that commonly cause symptomatic bonemetastases include kidney and thyroid cancer, andmultiple myeloma

Bone metastasis

Patients with bone metastasis from breast cancer havean average 2-year survival from the time of presentationwith their first bone lesion

More patients are living with bone metastases, and thusthe challenge is to improve their quality of life

Early detection and aggressive management ofmetastases is the goal

Maintain and maximize patients' quality of life andfunctional level

Currently, care is optimised in only a fraction of patientswith bone metastases

Bone metastasis

There are four main goals in managing patients wi thmetastatic disease to the skeleton:

pain relief

preservation and restoration of function

skeletal stabilization

local tumour control (e.g., relief of tumour impingement onnormal structures, prevention of release of chemicalmediators that have local and systemic effects)


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Spinal cord compression

Diagnosis is clinical

confirmation can only bemade radiologically

MRI is investigation of choice :

Thoracic 70%

Lumbar 15%

Cervical 10%

Sacral 5%


The finding of bilateral UMN signs should be consideredspinal cord compression until proved otherwise

SCC from metastatic cancer remains an important sourceof morbidity despite the fact that with early diagnosis,treatment is effective in 90% of patients

Malignant spinal cord compression is defined as thecompressive indentation, displacement, or encasement ofthe spinal cord's thecal sac by metastatic or locallyadvanced cancer

Any neoplasm capable of metastasis or local invasion canproduce malignant spinal cord compression


Response to nonsurgical therapy and the duration ofsurvival following treatment can vary considerably amongdifferent histological tumour types

The degree of pretreatment neurological dysfunction isthe strongest predictor of treatment outcome

Ambulation can be preserved in greater than 80% ofpatients who are ambulatory at presentation

Key to successful management is a heightenedawareness of signs and symptoms, specifically newlydeveloped back pain or motor dysfunction, leading toearly diagnosis and treatment.


Tumour type Frequency %

Breast cancer 29

Lung cancer 17

Prostate 14

Myeloma 4

Renal 4

Lymphoma 5

Sarcoma 2 Other 23

Leptomeningeal metastasis

CSF

TNM StagingT Primary tumours

T0 No palpable tumourT1 Tumour 2cm but < 5cmT3 Tumour > 5cm in great est dimension

T4 Tumour of any size fixed with direct extension to chest wall, skin, ribintercostal muscles, serratus anterior muscle (not pect oral muscle)

N Regional lymph nodes

N0 No palpab le homolater al lymph nodesN1a Palpable nodes, not felt to contain tumour

N1b Palpable nodes thought to contain tumourN2 Nodes > 2cm or fixed to one another or other structures

N3 Supracla vicular or infracla vicular nodes involved

M Distant metastases

M0 No evidence of distant metastasesM1 Distant metastases present including skin involvement beyond the breast area


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Survival by number of involved axillary nodes

Number ofpositive nodes

012-34-5

6-1011-1516-20

21 or more

Percent Surviving

100

40

20

1 2 3 4 5 Years after diagnosis

60

80

0

Lymph node surgery

Sentinel

Radioisotope/Blue dye directed sample

“Sample”

4-6 nodes from the lower axilla sampled

Level 1

Lateral to pectoralis minor

Level 2

Posterior to pectoralis minor

Level 3

Medial to pectoralis minor

Progression through lymph nodes

98.7% - orderly progression

54% - level 1 only

23% - levels 1 & 2

21% - levels 1, 2 & 3

1.2% - level 2 skipping level 1

0.1% - level 3 skipping levels 1 & 2

Who to stage for early breast cancer

1076 patients, Early Breast Cancer Trial

All were asymptomatic

All staged with CXR, US, bone scan

All “suspicious” findings explored further with CT, MRI orPET

Staging results

30 (2.8%) patients found to have dis tant metastases

130 (12.0%) suspected but not confirmed on CT, MRI or

PET7 of these 130 confirmed to have metastases within 6months

916 (85.2%) metastases excluded


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Risk factors for distant metastasis

> 3 involved lymph nodes (p=0.06)

> 10 involved nodes (p=0.002)

T3/4 tumour (p=0.08)

36/37 patients with metastatic disease had one of theserisks

36/269 (13.4%) with risk factors had metastasis

1/807 (0.12%) without risk factors had metastasis

Recommendation for staging

Tumour > 5 cm

> 3 Nodes (clinically palpable nodes)

Clinical suspicion

All should have CXR, US, bone scan

1 in 7.5 will have metastases

1 in 800 will be missed

Recommendation for staging

CT or MRI are used if there is a clinical suspicion ofmetastasis

Tumour markers? (not as part of staging …)

Breast cancer treatment

Surgery

Radiotherapy

Hormone therapy

Chemotherapy

Biological therapy

Everything else

Breast cancer: Radiotherapy

Mandatory for the conserved breast

May be used as an alternative to surgery to the axilla

Radiotherapy to the chest wall and/or axilla reduces thelocal recurrence rate in patients who have heavy lymphnode infiltration

Radiotherapy to lymph node areas improves causespecific survival

NCN Guidelines for radiotherapy

Breast conserving surgery

All patients

Post mastectomy

All tumours > 5cm

Tumours deep in the breast where surgical clearance is3mm or less

All patients with 4 or more lymph node metastases


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014 Centre for Cancer Education 1

Use of tamoxifen: Oxford overview 1995

% R e

d u c

t i o n

i n r e c u r r e n c e

% R e

d u c

t i o n

i n m o r t a

l i t y

Aromatase inhibitors

Only of value in POSTMENOPAUSAL women

Some advantages compared to tamoxifen for disease-free survival

No clear advantage in survival except in extendedadjuvant setting

Trial data for aromatase inhibitors ab initio or after 2/3 or5 years of tamoxifen

0 10

20

30

40

50

60

21Invasive*

53

Tamoxifen(n=2598)

Anastrozole(n=2618)

26

5 DCIS

48Invasive*

Numberofcases

5 DCIS

*p=0.0 01 for invasive cancers

HR

0.47

0.58

HR+

95% CI

(0.29 –0.75)

(0.38-0.88)

p-value

0.001

0.01ITT

Incidence of contralateral breast cancer Adjuvant chemotherapy

Use of cytotoxic drugs to reduce the risk of recurrenceand death

Trials have shown incremental advantages wi th theaddition of:

Newer drugs

CMF > Surgery alone

Anthracyclines > CMF

Taxanes > Anthracyclines

Different combination strategies

Increase in dose density

Block sequential regimens

Effect of polychemotherapy vs. control

Annual death rates Years 0-4 Years 5-9 Years 10+

A/E+ 4.40% (SE 0.12) 3.63% (SE 0.17) 2.87% (SE 0.36)CMF 5.07% (SE 0.15) 3.81% (SE 0.20) 4.16% (SE 0.59)

Deaths/woman-years

A/E+ 1246/28305 470/12940 64/2233CMF 1219/24067 372/9758 49/1177

100

80

60

40

00 5 10 years

%

80.2%

68.0%76.7%

3.6% ( SE 0.8)

4.6% ( SE 1.2)63.4%

Actuarial estimate and SE: – allocated A/E+

– allocated CMF

Anthracycline vs. CMF: Overall survival


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TAC

FAC

0 6 12 18 24 30 36 42 48 Months

Number at Risk TAC FAC

745 741 732 718 700 393 171 24 1 746 738 728 713 678 375 171 33 1

50

60

70

80

90

100

% A

l i v e

# Events RR p-value

TAC 570.76 0.11

FAC 76

Total 133

92%

87%

Addition of taxanes: Overall survival Breast cancer prevention

Mastectomy

Ovarian ablation

Drugs

Surveillance

Risk reducing mastectomy

Reduces risk of breast cancer because it reduces volumeof breast tissue

In patients with BRCA mutations, risk is reduced to 1%

Surgical oophorectomy in BRCA1 carriers

Tamoxifen: NSABP P1 Trial

13388 women at increased risk of breast cancer

Tamoxifen 20 mg/day Placebo dailyx 5 years x 5 years(6681) (6707)

Tamoxifen: NSABP P1 Trial


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NSABP P1 Trial: endometrial cancer NSABP P1 Trial: Results

Tamoxifen advantages

49% less invasive cancer (p

case4 breastcancer handout

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