Breast Cancer Patient Issuesin Family Practice:

An Interactive Session

AcknowledgementsContent Development Committee

Sunil Verma, MD, MSEd, FRCPC Lisa Del Giudice, MSc, MD, CCFP Medical Oncologist, StaffDivision of Medical Department of Family MedicineOncology/Hematology Sunnybrook & Women's College Toronto Sunnybrook Regional Health Sciences Centre Cancer Centre Assistant ProfessorAssistant Professor, University of Toronto University of Toronto Toronto, OntarioToronto, Ontariosunil.verma@sw.ca

Novartis Pharma Canada Inc gratefully acknowledges the commitment and dedication of the Content Development Committee to the development of this program

Objectives

To recognize the risk of breast cancer recurrence and the common health problems faced by women with history of breast cancer

To review the requirements for complete follow-up care of women with history of breast cancer

To discuss the recent advances in the field of breast cancer, specifically in the arena of endocrine therapies

To describe the reasons for referrals back to the cancer centre for women with history of breast cancer

National Cancer Institute of Canada/www.cancer.ca.Fisher et al. J Natl Cancer Inst Monographs 2001.

*American Joint Committee on Cancer. Handbook for Staging of Cancer 1993.

Breast Cancer

2004 breast cancer rates from the National Cancer Institute of Canada

– 21,200 new cases diagnosed in Canada– 5,200 deaths

Second leading cause of cancer death in women Outcome is directly related to stage at diagnosis, eg,

survival after 5 years* – Stage I disease 95%– Stage II disease 70%-85%– Stage III disease 50%-52%– Stage IV disease 17%

2004 Canadian Breast Cancer Incidence Rates

Of the 21, 200 new cases

16,700 (79%) were

age ≥50 years 11,000 (52%) were

age ≥60 years

www.cancer.ca

Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years

0

Year

105

90

75

60

45

30

15

1950 1960 1970 1980 1990 2000

An

nu

al d

eath

rat

ep

er

10

0,0

00

wo

men

UK

USA

Reprinted with permission from Elsevier Science. Lancet 2000.

Breast Cancer Presentation

Early Breast Cancer

Locally AdvancedBreast Cancer

Metastatic Breast Cancer

Early Breast Cancer Treatment Schema

SURGERY

AdjuvantChemotherapy

AdjuvantRadiation

AdjuvantEndocrine

Early Breast Cancer Treatment Schema

SURGERY

Follow-Up

AdjuvantChemotherapy

AdjuvantRadiation

AdjuvantEndocrine

Case No. 1

45-year-old female patient R breast lump originally diagnosed March 2004 R breast lumpectomy and node dissection 6 weeks

ago Pathology

– 2.5 cm size– Tumour Grade II/III – Estrogen receptor -ve/Progesterone receptor -ve

(hormone receptor negative)– Lymph nodes 3/12 involved

Case No. 1

What is her recurrence risk? – Without any further treatment?– With chemotherapy?

Prognostic Factors

In order for us to assess the recurrence risk we need to review certain prognostic factors

These prognostic factors include– Lymph node status– Tumour size– Tumour grade– Receptor status

Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy

0

10

20

30

40

50

60

70

58.7%

33.4%

Per

cen

tag

e o

f p

atie

nts

(%

)

No additional therapy

Chemotherapy

Case No. 1: Survival Benefit from Chemotherapy

(Alive in 10 years)

0

10

20

30

40

50

60

70

80

51.0%

70.1%

Per

cen

tag

e o

f p

atie

nts

(%

)

No additional therapy

Chemotherapy

Case No. 1: Conclusion

Adjuvant chemotherapy results in– Lowering the recurrence risk, and– Improvement in survival

The patient in this case with early breast cancer should be considered for a medical oncology opinion for possible adjuvant chemotherapy

Exciting Advances in Breast Cancer Management

Chemotherapy

Molecular therapy

Endocrine therapy

Chemotherapy

Early breast cancer – Taxanes

• Paclitaxel• Docetaxel

– Dose-Dense • Every 2 weeks (compared to every 3 weeks

of regular therapy)– Neoadjuvant

Neo-Adjuvant Chemotherapy

SURGERY

Neo-AdjuvantChemotherapy

AdjuvantRadiation

AdjuvantEndocrine

Molecular Therapy

Advances in Endocrine Therapy:“A Revolution in the Treatment of

Breast Cancer”

Case No. 2

64-year-old female patient Recent dx of L sided breast cancer Mastectomy and axillary nodal dissection (AND) Pathology

– Tumour Size 1.2 cm– Tumour Grade II/III– Estrogen receptor +ve/progesterone receptor +ve

(hormone receptor +ve)– Lymph node negative (0/18)

Case No. 2

What are the different treatment strategies available for this patient?

– Tamoxifen for 5 years

Case No. 2

What are the benefits of tamoxifen? What are the toxicities related to tamoxifen?

Tamoxifen: Improvement in Disease-Free Survival

Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science.

Years

100

% R

ecu

rren

ce-f

ree

90

80

60

40

20

05 10+0

Node -ve: 14.9% SD 1.4: 2P<0.00001Node +ve: 15.2% SD 2.5: 2P<0.00001

Node -ve

Node +ve

87.4

79.274.9

75.6 64.3

59.758.3

44.5

70

50

30

10

Absolute Recurrence Reduction

Tamoxifen (~5 y)

Placebo

Placebo

Tamoxifen (~5 y)

Recurrence as First Event

Toxicity of Tamoxifen

Endometrial cancer Venous thrombosis Hot flashes Vaginal dryness/bleeding

Case No. 2

What are the different treatment strategies available for this patient?

– Tamoxifen for 5 years– Aromatase inhibitor [AI] for 5 years– Tamoxifen for 2 -3 years followed by an AI to

complete 5 years of treatment– Tamoxifen for 5 years followed by an AI for 5

years

Winer et al. JCO 2005.

Case No. 2: Further Questions

What is the mechanism of action of aromatase inhibitors?

What are the different classes of aromatase inhibitors?

Is there any evidence that aromatase inhibitors– Are better than tamoxifen?– Can be used within the first 5 years in sequence

with tamoxifen?

Mechanism of Action

Smith et al. N Engl J Med 2004.

Classes of Aromatase Inhibitors

Type 1(Steroidal Inactivator)

Type 2(Nonsteroidal Inhibitor)

• Exemestane (Aromasin) • Anastrozole (Arimidex)

• Letrozole (Femara)

Tamoxifen vs. Aromatase Inhibitors in Early Breast Cancer

First Line

ATAC Trial (Anastrozole)

BIG 1-98 Trial (Letrozole)

ATAC (Anastrozole)

ATAC Trialists’ Group. Lancet 2005.

+

Postmenopausal women with invasive breast cancerPostmenopausal women with invasive breast cancer

Surgery Surgery radiotherapy radiotherapy chemotherapy chemotherapy

Randomization 1:1:1 for 5 yearsRandomization 1:1:1 for 5 years

Anastrozole 1mg od+

Tamoxifen placebo

Anastrozole placebo+

Tamoxifen 20mg od

Anastrozole 1mg od+

Tamoxifen 20mg od

n=3125 n=3116 n=3125

ATAC Trial (Anastrozole): Efficacy

Anastrazole shown to be superior to tamoxifen– Improved Disease Free Survival (DFS)– Contralateral breast cancer

No difference in Overall Survival (OS)

BIG 1-98 Trial (Letrozole): Efficacy

Early results from this study show that– Letrozole is also superior to tamoxifen for

• Disease Free Survival• Distant recurrences (Systemic Disease Free

Survival)

Aromatase Inhibitor Toxicity

In favour of Aromatase Inhibitors– Endometrial cancer– Vaginal bleeding/discharge– Thromboembolic disease

In favour of tamoxifen– Arthralgias– Osteoporosis

Case No. 3

64-year-old female patient Hx of L sided breast cancer Original dx 2002 Mastectomy and AND Pathology

– Tumour Size: 1.2 cm– Tumour Grade: II/III– ER +ve/PR +ve– Lymph node negative (0/18)

On tamoxifen since 2002

Case No. 3

The different treatment strategies available for this patient are

– Complete tamoxifen for 5 years– Tamoxifen for 2 years followed by exemestane

(an AI) to complete 5 years of therapy– Tamoxifen for 5 years followed by letrozole (an

AI) for another 5 years of therapy

Switching From Tamoxifen to Aromatase Inhibitors

IES Trial (Exemestane)

IES Schema

RRAANNDDOOMMIIZZAATTIIOONN

• Postmenopausal women

• Early ER+ breast cancer

• Disease free after adjuvant tamoxifen

20 mg po qd × 2-3 years

• 2-3 yearstamoxifen

20 mg po qd

• 2-3 yearsexemestane20 mg po qd

5 years total therapyCoombes et al. N Engl J Med 2004.

IES Trial (Exemestane): Efficacy

Exemestane was superior to tamoxifen– Disease Free Survival (DFS)– Distant DFS

No difference in OS (Overall Survival)

IES Trial (Exemestane):Toxicity

In favour of exemestane– Vaginal bleeding/discharge– Endometrial cancer– Thromboembolic disease

In favour of tamoxifen– Arthralgia– Osteoporosis

Summary

Many options available for first-line treatment of hormone receptor positive early breast cancer

– Tamoxifen for 5 years, or– Anastrozole (AI) for 5 years, or– Letrozole (AI) for 5 years, or– Tamoxifen for 2 years followed by exemestane

(AI) to complete 5 years of therapy

Winer et al. JCO 2005.

Summary (cont’d)

The optimal choice of therapy is dependent on – Patient’s underlying health– Tumour-related factors– Patient preference

Extending Endocrine Treatment Beyond Five Years of Therapy

MA.17 Trial (Letrozole)

Case No. 4

63-year-old female patient Hx of breast cancer, originally dx 5 years ago L lumpectomy and AND Pathology at that time:

– Tumour Size 2.5 cm – Tumour Grade III/III – Estrogen receptor +ve/progesterone receptor -ve– Lymph node 2/14 +ve

Followed by chemotherapy and radiation tx Received tamoxifen for 5 years Completed tx 2 months ago

Case No. 4

What is her risk of recurrence now after completing 5 years of therapy with tamoxifen?

Should we keep her on tamoxifen longer?

Recurrences Breast Cancer Deaths

More Than Half of Breast Cancer Recurrences and Deaths Occur Post-Tamoxifen

Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000.

Years

85.2

76.1

68.2

73.7

62.7

54.9

68%

55%

0

20

40

60

80

100

0 5 10 15

TamoxifenControl

15% 17%

0

20

40

60

80

100

0 5 10 15

73%64%

80.9

73.087.8

73.2

64.064.0

Years

TamoxifenControl

9% 18%

91.4

% o

f p

atie

nts

% o

f p

atie

nts

Case No. 4: Recurrence Risk

In this case situation, on average, – 70% of patients will be alive and without disease

at 5 years– There is still a 26% chance of relapse within

next 5 years

NSABP B-14

Fisher et al. J Natl Cancer Inst 2001.

DFS

100

90

80

70

60

50

% o

f p

atie

nts

0 5

PlaceboTamoxifen

Years7

OS

0 5Years

100

90

80

70

60

507

% o

f p

atie

nts

PlaceboTamoxifen

Tamoxifen demonstrated higher rates of endometrial cancer, ischemicheart disease, and cerebrovascular disease.

82%

78%

94%

91%

P=0.03

P=0.07

1 2 4 63 1 32 4 6

No benefit of extending tamoxifenbeyond 5 years of therapy

Case No. 4

Are there other therapeutic options available for this patient?

Extended adjuvant letrozole

Adjuvant tamoxifen

Rationale for the MA.17 Extended Adjuvant Trial

Lack of benefit when adjuvant tamoxifen treatment is extended beyond 5 years

Increasing risk for long-term adverse effects (thromboembolism, endometrial hyperplasia/cancer, hot flashes, vaginal/urinary symptoms)

Need to extend DFS/OS beyond adjuvant tamoxifen

Goss et al. N Engl J Med 2003.

Trial Design of MA.17

Goss et al. N Engl J Med 2003.

Randomization(All patients disease-free)

Tamoxifen

Placebo qd

Letrozole 2.5 mg qd

Approx. 5 years adjuvant 5 years extended adjuvant

0–3months n=2575

n=2582

Letrozole (MA.17) Efficacy

Letrozole was superior to placebo– DFS (Disease Free Survival)– Distant DFS– Overall Survival

• difference in Lymph Node positive patients only

P=0.04

Node-Positive Node-Negative

P=0.24

Overall Survival MA.17

0

20

40

60

80

100

Time from randomization (months) 0

12921276

10

12651250

20

972964

30

572571

40

275283

50

9393

60

35

0

20

40

60

80

100

Time from randomization (months)

Femara Placebo

0

11711189

10

11441157

20

875877

30

508500

40

255243

50

8175

60

33

Per

cen

t

Letrozole Placebo

Per

cen

t

Letrozole Placebo

No. at Risk

Adapted from Goss. ASCO 2004.

While OS was not improved in node-negative patients, a similar reductionin local recurrences, new primaries, and distant recurrences occurred as in

the node-positive patients

Letrozole (MA.17) Toxicity

Letrozole compared to placebo Letrozole therapy associated with

– Hot flashes– Vaginal bleeding/discharge– Osteoporosis

Adapted from Goss. ASCO 2004.

Case No. 4: Summary

Patients such as in this case, who have completed 5 years of therapy on tamoxifen, should

– Be referred back to the cancer centre The medical oncologist will discuss extended therapy

for these patients This discussion may involve

– Recurrence risk– Patient’s co-morbidities– Patient preference

Summary: Use of Aromatase Inhibitors

Aromatase inhibitors in adjuvant setting– Literature specific for post-menopausal women– Effective in preventing recurrence, reduction in

distant metastasis and new contralateral breast cancer

– Effective as first-line adjuvant, sequence, and extended therapy

– Overall survival improvement seen only in node-positive patients with 5 years of letrozole in the extended setting

– Long-term safety data remains to be studied

Best Adjuvant Strategy: Remains to be Seen

Aromatase inhibitors– As neoadjuvant?– After 2-3 yrs of tamoxifen?– after 5 yrs of tamoxifen?– after 5 yrs of AI therapy?– Duration of AI therapy?– Only for high-risk breast cancer?

Follow-Up of Patientswith History of Breast Cancer

Early Breast Cancer Treatment Schema

SURGERY

AdjuvantChemotherapy

AdjuvantRadiation

AdjuvantEndocrine

Follow-Up

Case No. 5

54-year-old female patient Dx with early stage breast cancer 2 years ago Received chemotherapy with an anthracycline-

containing regimen (CEF)– Cyclophosphamide– Epirubicin– Fluorouracil

Case No. 5

What is the role of family physicians (FPs) in following these patients?

Why is it important to follow patients with previous history of breast cancer?

What are the requirements for appropriate follow-up?

Role of Family Physician

FPs remain the primary care givers for most of these patients

FPs may provide follow-up as– Sole provider of care– In conjunction with the cancer centre

Who Should Do the Follow-up?

Ontario Study– Randomized breast cancer follow-up to

• Cancer centres• Family physicians

Results– No difference in patient outcome

• Serious clinical events

Grunfeld et al. PASCO 2004.

Why Follow Patients?

Follow-up may help– Provide adequate psychosocial support and

counseling– Detect recurrent and metastatic disease– Detect other malignancies– Monitor toxicities related to current or previous

treatment

Canadian Steering CommitteeGoals of Follow-Up

Three major objectives of follow-up care– Support and counseling– Detection of disease relapse locally and distant– Surveillance for second malignancies

Frequency of Follow-Up

Bari Consensus Conference (1995) recommendations

– Visits every 3 months for the first 2 years, then– Every 6 months for the next 3 years, then – Annually thereafter

Available Guidelines

Canadian Steering Committee on Clinical Practice Guidelines (Canadian Task Force)

American Society of Clinical Oncology (ASCO)

Canadian Steering Committee on Clinical Practice Guidelines. CMAJ 1999.American Society of Clinical Oncology. JCO 1998.

Summary of Guidelines

History and physical– Every 3-6 months first 3 yrs after primary

therapy– Then q 6 months for 2 yrs– Then annually

Annual mammogram Encourage monthly BSE Educate re: recurrence symptoms Regular pelvic exams

Canadian Steering Committee on Clinical Practice Guidelines. CMAJ 1999.American Society of Clinical Oncology. JCO 1998.

Summary of GuidelinesDo Not Do Routinely

CBC, renal function tests, liver function tests, albumin, protein, calcium

Chest X-ray Bone scan Liver ultrasound CT Tumour markers: CEA, CA 15-3

Canadian Steering Committee on Clinical Practice Guidelines. CMAJ 1999.American Society of Clinical Oncology. JCO 1998.

Follow-up for Breast Cancer Patients On Endocrine Therapies

Bloodwork– No need for routine blood work

Bone mineral density (BMD)– Of particular importance for patients on

aromatase inhibitors • Recommend baseline, then annually

Follow-up for Breast Cancer Patients On Endocrine Therapies (cont’d)

Ophthalmologic evaluation– Symptom driven– If previous history – annual exam

No role for other routine investigations – Including pelvic or abdominal U/S, Doppler, etc.

Common Health Issues Among Breast Cancer Patients

Common Health Issues

Cardiac toxicity Osteoporosis Early menopause Secondary cancers

Case No. 5 (cont’d)

Patient now has increasing SOB with exertion– What other features on history and physical

examination are important?– What investigations are critical to help us with

the diagnosis?

Cardiac Toxicity –Chemotherapy Related

Anthracyclines– Daunorubicin, doxorubicin, idarubicin, epirubicin,

and mitoxantrone Toxicity effects

– Acute (during administration)• Arrythmias, pericarditis-myocarditis

– Early (Several days to mos following)• CHF, with peak at 3 mos after last dose

– Late (years to decades following)• CHF may develop up to 10-12 yrs after last

anthracyline dose

Cardiac Toxicity – Anthracyclines

Risk factors for the development of anthracycline cardiac toxicity

– Cumulative dose – strongest risk factor– Age– Prior irradiation– Concomitant administration of other agents– Previous history of cardiac disease

Cardiac Toxicity – Other Therapies

Aromatase inhibitors– Long-term cardiac toxicity remains to be studied

with these agents Herceptin

Osteoporosis

Hormone-dependent osteoporosis– Early menopause– Chemotherapy-induced premature ovarian

failure– Endocrine treatment

Hormone-independent osteoporosis– Direct effect of chemotherapy– History of breast cancer

Management of Osteoporosis forPatients on Aromatase Inhibitors

Surveillance– Annual BMD– Height measurements

• If needed: T + L Spine X-rays– Risk factor assessment

Therapy– Bone hygiene

• Calcium 1500 mg/d + Vitamin D 800 I.U. supplement– Bisphosphonate therapy

• Early initiation of bisphosphonate therapy if» BMD t score <2.5» Progressive bone loss

Hillner et al. JCO 2003.

Early Menopause

Fertility issues Menopausal symptoms

– Treatment related– Non-treatment related

Osteoporosis (previously discussed)

Secondary Cancers

Incident case Breast cancer

– New primary cancer• Risk about 1%

per year– Recurrence

• Local• Metastatic

Other cancers Treatment independent Secondary to treatment

– Chemotherapy– Radiation – Endocrine

Other Concerns

Lymphoedema– Referrals to supportive care services

Family members– Screening for breast cancer– Screening for other cancers– Genetic assessment

Case No. 5 (cont’d)

Patient now presents with back pain over the last 4 months

Pain located in lower thoracic/upper lumbar area

Case No. 5 (cont’d)

When should the FP refer the patient back to the cancer centre?

What are some concerning symptoms associated with back pain?

What are the common sites of distant metastasis? How should we investigate?

When Should FPs ReferPatients to Cancer Centre?

Cancer related– New breast lump or local lymphadenopathy

• New primary breast cancer• Cancer recurrence

– Concerning distant symptoms– Secondary cancers

When Should FPs Specifically Consult Medical Oncology?

Treatment related– New endocrine treatment for follow-up

population– Toxicities– Patient driven

Early Breast CancerRole of Family Physicians

SURGERY

AdjuvantChemotherapy

AdjuvantRadiation

AdjuvantEndocrine

Follow-Up

Family physicians

Conclusions

There have been some key advances in the management of breast cancer in the last few years

Regular and appropriate follow-up care is essential for patients with history of breast cancer

Conclusions

Family physicians play an integral role in the management of these patients

It is important to refer patients to cancer centre – To evaluate any specific concerns, or – To review if they are suitable candidates for new

therapies