Breast cancer - current concepts

BREAST CANCER

DR. R. RAJKUMAR M.D. D.M.

Dr. R. RAJKUMAR M.

Breast Cancer

• Incidence:

– Invasive breast cancer 1

• 1.4 million new cases in 2008

– Past 25 years

• Breast cancer incidence rates have risen

globally

• Highest rates occurring in the westernized

countries

–Change in reproductive patterns

– Increased screening

–Dietary changes

–Decreased activity

• Mortality

– Mortality has been decreasing

– Especially in industrialized countries.1 American Cancer Society

BREAST CANCER IN INDIA

• Around 1 lakh cases /yr

• Peak incidence - 55-59/yr

• Age shift

• Rising numbers

• Late presentation

• Lack of awareness and screening

• Aggressive cancers in young

Age shift – cases in seen 30’s& 40’s

• Young onset breast cancer

• High grade (aggressive) tumors

• High proliferative tumors

• ER negative tumors

• “Triple negative” (ER-/PR-/HER2-) tumors

INDIAN Women More Likely to Have:

Importance of Pathology: Not all Breast Cancers Are the Same!!

Estrogen

Receptor (ER) +

75% of Breast

Cancer

HER-2 +

20-25% of Breast

Cancer

Tumor ER and HER2 status critical in selecting therapy in

both early stage and metastatic breast cancer

Treatment of Early Stage Breast Cancer

• Breast cancer most curable when detected early

– Micrometastases (undetectable) can exist at time of diagnosis in many patients, leading to eventual recurrence

• Multidisciplinary care critical for best outcomes

– Surgery

– Radiation therapy

– Adjuvant systemic (drug) therapy reduces risk of recurrence and death

» Should be tailored to the patient and tumor

No surgery

mastectomy

chemotherapy + endocrine therapy

chemotherapy + endocrine therapy +

HER2 targeted therapy

Incremental Benefit of Adjuvant

Treatments in Early Stage Breast

Cancer in USA

Survival

Adjuvant (Early Stage) Endocrine Therapy in Breast Cancer

• Tamoxifen has substantial clinical efficacy, less cost, and several decades of use throughout world

– Still the standard for premenopausal

– Reasonable for many postmenopausal

– Longer duration (> 5 years) may benefit many patients

• Adjuvant aromatase inhibitors: small differences in recurrences (and in some trials deaths)

– Side effects different

• Ovarian suppression effective as a sole treatment

– Still unclear whether it adds to chemo/tamoxifen

Early Breast Cancer Trialists’ Collaborative Group

Clinical Trials of Tamoxifen in Early Stage Breast Cancer: Disease-free Survival

ER Negative ER Positive

Adjuvant tamoxifen

significantly reduces

recurrence in ER positive

breast cancer

tamoxifen

control

Tamoxifen effective in both pre- and postmenopausal women

Adjuvant tamoxifen

doesn’t impact

recurrence in ER

negative breast cancer

Adjuvant (Early stage) Chemotherapy in Breast Cancer

• Adjuvant chemotherapy reduces recurrences and deaths

– Reducing dose from that proven to be effective in clinical trials reduces benefit

– Chemotherapy drugs have significant side effects

• For unselected patients/tumors:

– anthracyclines better than CMF regimens

– taxanes add to anthracyclines – expensive

• Not all patients/tumors benefit from chemotherapy!

• ER-negative, high grade, HER-2+ tumors get most benefit from chemotherapy

Chemotherapy Dose MattersAdjuvant Chemotherapy - 20 Year Follow-up

Milan StudyBonadonna G et al, N Engl J Med 332: 901-6,1995

0.9

1.0

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.05 10 15 20

Years after Mastectomy

Disease-free survival

Pro

ba

bili

ty o

f R

ela

pse

-fre

e S

urv

iva

l

5 10 15 20

Years after Mastectomy

0.9

1.0

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Overall survival

Pro

ba

bili

ty o

f O

ve

rall

Su

rviv

al

>85% of dose

<65% of dose

Control

65-84% of dose

If chemotherapy is given, it should be given at full dose

Adjuvant (Early Stage) HER-2 Targeted Therapy

• Anti-HER2 monoclonal antibody trastuzumab(Herceptin) for 1 year is standard

– Reduces recurrence by 1/2 & deaths by 1/3 when added to chemo in early stage breast cancer

– Trastuzumab going off patent soon, and prices will drop

• All regimens include chemotherapy in addition to HER2 targeting therapy

Molecular classification & Prognosis:

• Luminal A= Best prognosis

• Luminal B

• Luminal C

• Normal breast like

• Her 2+

• Basal like= Worst= Triple Negative

14

SUBTYPE

Type Importance

Luminal A ER +, Best overall

survival, Best DFS

Luminal B ER,Her2+,Intermediate

Her 2 +ve ER-, Intermediate

Basal like ER-,PR-, Her2 - Worst

15

BREAST CANCER

Stage IV

Any T any N M1

Examples of distant mestastatic disease

BREAST CANCERSites of distant

metastases

Skin

Liver

Bone

Pleura

Lung

Lymph nodes

Brain

Treatment of Metastatic Breast Cancer

• Metastatic breast cancer is not curable, but can be very treatable

• Goals:

–Control and regression of disease

–Prolongation of life

–Improvement in symptoms and quality of life

Choices in the Treatment of Metastatic Breast Cancer

• Choice of treatment is based on many factors:

–Patient age, menopausal status, general health and functional status

–Tumor ER status, HER-2 status

–Previous treatments

–Extent and sites of disease

– Available therapies in the patient’s country

Breast Cancer Systemic Therapies

• Drug treatments that can attack cancer cells throughout the body

–Endocrine therapy

–Chemotherapy

–Biologically-targeted therapy

Endocrine Therapy in Breast Cancer

Estrogen

Cell

Growth

and

Division

Estrogen

Receptor

SERMS (tamoxifen),

SERDS Aromatase inhibitors, ovarian

suppression

Endocrine therapy effective only in ER-positive breast cancer

ER/PR staining: CRITICAL IN SELECTING THERAPY!

Endocrine Therapy for Metastatic Breast Cancer

• Endocrine therapy is the preferred choice for ER+ metastatic breast cancer

– Less side effects than chemotherapy

• Exceptions:

– Concern or proof of endocrine resistance

– Need for fast response (location, symptoms)

Hormonal Therapies (FDA indications)

• 1st line therapy:

–Tamoxifen, anastrozole (Arimidex), letrozole (Femara)

• 2nd line therapy:

–Fulvestrant (Faslodex), toremifene (Fareston), exemestane (Aromasin)

• “Palliative”

–Goserelin (LHRH analog, Zoladex)

Chemotherapy

Treatment of Metastatic Breast Cancer: Cytotoxic Agents

• Anthracyclines (doxorubicin, liposomal doxorubicin)

• Cyclophosphamide

• Taxanes (paclitaxel, docetaxel)

• Antimetabolites (5-FU, capecitabine)

• Gemcitabine

• Vinorelbine

• Carboplatin/cisplatin

European School of Oncology Guideline: Chemotherapy for Metastatic Breast

CancerCardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009

• Sequential single agent chemotherapy generally preferred choice

– Less toxicity than combination chemo

– No data to support optimal sequence

• Combination chemotherapy reserved for patients with:

– rapid clinical progression

– life-threatening visceral metastases

– need for rapid symptom/disease control

• Chosen regimen should be evidence-based, with proven efficacy and acceptable toxicity

Biologically-Targeted Therapy

Her2/neu status

• Membrane-associated tyrosine kinase receptor (aka erbB2) related to EGF

–Expressed in breast cancers, DCIS, and some other tissues such as heart

–Overexpressed in 25-30% of breast cancers

–Associated with more aggressive disease and worse prognosis

Measurement of Her2/neu

• Measured by immunohistochemistry (IHC)

– Graded 0, 1+, 2+, or 3+

– Based on characteristics of staining

– 0-1 = negative

– 2 = indeterminant, should be followed with FISH (fluorescent in situ hybridization) to determine status (amplified/not amplified)

– 3 = positive

• Fluorescence In Situ Hybridization (FISH) correlates with response to Herceptin, but more expensive

Four US FDA-Approved Drugs with HER-2 as a Target

cell division

HER-2

nucleus

cancer cell

Trastuzumab (Herceptin)

Anti-HER-2 Antibody

Lapatinib (Tykerb)

Dual HER-1/HER-2

Tyrosine Kinase Inhibitor

Pertuzumab

Anti-HER-2 Antibody

T-DM1

Antibody-Drug

Conjugate

20-25% of breast

cancers overexpress

HER2

Only effective for HER2+ breast

cancer

Trastuzumab (Herceptin)

• Humanized monoclonal antibody against her2/neu

• FDA approved for metastatic breast cancer in 1998

• Responses in patients with her2/neu positive breast cancer

– IHC 3+

– FISH positive

• Single agent therapy has 26% response rate as 1st

line therapy

• May be given as an IV infusion weekly or every 3 weeks

European School of Oncology Guideline: HER2 Targeted Therapy

for Metastatic Breast CancerCardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009

• Anti-HER2 therapy should be offered early to all HER2+ metastatic breast cancer patients unless contraindicated (or unavailable)

• Optimal duration of anti-HER2 therapy for metastatic breast cancer (when to stop) unknown

Complications of Breast Cancer Bone Metastases

Pain

Spinal cord

compression

Radiation

therapy

Orthopedic

surgery

Hypercalcemia

Fractures

The bone is the initial site of recurrence in 35-40% of breast cancer patients

European School of Oncology Guideline: Bone Metastases in Breast Cancer

Cardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009

• Bone modifying agents should be routinely used in combination with other systemic therapy in patients with bone metastases

– Bisphosphonates (pamidronate, zoledronic acid)

– RANK ligand inhibitor (denosumab)

• Agents should be started early, if possible before onset of bone symptoms

• Should be continued even in presence of disease progression

Zoledronic Acid (Zometa)

• Bisphosphonic acid – inhibitor of osteoclastic bone resorption

• Indicated for solid tumor patients with bone metastases

• 4 mg IV over 15-30 minutes

• Check serum creatinine before each administration

• Comparable in efficacy to pamidronate

•Rosen LS, Cancer J 7:377, 2001

Systemic Treatment of Breast Cancer: Summary

• Main principles of modern oncology

– Multidisciplinary treatment

– Evidence-based medicine

– Individualized (tailored) therapy

• Keep in mind goals of therapy

– Adjuvant: curative intent

– Metastatic: incurable but treatable

• Include psychosocial and supportive care and symptom-related interventions

• Include patient preferences and active participation

– Patients, families and caregivers should be invited to participate in decision-making