CLINICAL MANAGEMENT CLINICAL MANAGEMENT OF BREAST CANCEROF BREAST CANCER

Author: Andrea Spinazzola, MD

Group: Prof. Nancy Hynes

Clinical seminar 05/11/2014

STATISTICS U.S. 2014One in 4 deaths is due to cancerEstimated new cancer cases: 1,665,540. Estimated deaths: 585,720Average lifetime breast cancer risk for a woman 12.3% (1 in 8 women)

Siegel R, CA Cancer J Clin 2014

FEMALE BREAST ANATOMY

The bulk of the breast tissue is adipose tissue interspersed with connective tissue

Breast ducts comprise only about 10% of the breast mass

Genetic predisposition (15%)

Genetic mutation (5%): BRCA1, BRCA2, PALB2

Exposure to estrogens (endogenous and exogenous)

Ionising radiation

Dense breast

Low parity

Obesity

Age

BREAST CANCER RISK FACTORS

BREAST SELF-EXAM

SIGNS AND SYMPTOMS

5

Redness or pitting of the skin (skin of an orange)

PAGET’S DISEASE INFLAMMATORY BREAST CANCER

SCREENING GUIDELINES- GENERAL POPULATION -

NCCN 2014: annual mammography age 40 years - not established

ACS 2014: annual mammography age 40 years - as long as good health

USPSTF 2009: biannual mammography age 50-74 years

ESMO 2013: biannual mammography age 50-69 years

Cancer

Microcalcification

IS SCREENING REALLY USEFUL?

Miller AB, BMJ 2014

89.835 women aged 40-59 randomly assigned to mammography (five annual mammography screens) or no mammography 25 years follow-up End-point: deaths from breast cancer

Breast cancer specific mortality Breast cancer specific mortality from cancers diagnosed in screening period

Conclusion: Annual mammography in women aged 40-59 does not reduce mortality from breast cancer beyond that of physical examination when adjuvant therapy for breast cancer is freely available.Overall, 22% of screen detected invasive breast cancers were over-diagnosed

STAGING WORKUPHistoryMenopausal statusPhysical examination (including regional nodes)Full blood count, liver and renal function tests

BiopsySerum tumor markers CEA, Ca15.3Chest + Abdomen CTBone scintigraphy

TNM (simplified)T0 No evidence of primary tumorTis Carcinoma in situT1 Tumor ≤20 mm in greatest dimensionT2 Tumor >20 mm but ≤50 mm in greatest dimensionT3 Tumor >50 mm in greatest dimensionT4 Tumor of any size with direct extension to the chest wall and/or to the skin

pN0 No regional lymph node metastasis identified histologicallypN1 Micrometastasis, metastases in 1–3 axillary lymph nodespN2 Metastases in 4–9 axillary lymph nodes

pN3 Metastases in ≥10 axillary lymph nodes, or metastases in infraclavicular (level III axillary) lymph nodesM0 No clinical or radiographic evidence of distant metastasesM1 Distant detectable metastases

Breast cancer mortality by stage (source: ACS)

Stage grouping system

5-Year Relative Survival(source: NCI)

PATHOLOGICAL REPORT

Histological type Ductal Carcinoma In-Situ (DCIS) Lobular Carcinoma in Situ (LCIS) Infiltrating Ductal Carcinoma (IDC) Infiltrating Lobular Carcinoma (ILC) Special types:

endocrine responsive: Cribriform, Tubular, Mucinous endocrine non-responsive: Apocrine, Medullary, Adenoid Cystic, Metaplastic

Margins: >1 mm for the invasive component; >2 mm for DCIS

Grade

PATHOLOGICAL REPORT

Immunohistochemistry

ER, PgR

Ki-67 (MIB-1 antibody)

HER2

TILs in TNBC? Loi S, Ann Oncol 2014; Ali HR, Ann Oncol 2014; Adams S, JCO 2014

INTRINSIC SUBTYPES

A: copy number alteration

B: most commonly mutated cancer-related genes

Ades F, JCO 2014

Intrinsic subtype

Clinico-pathologic surrogate definition

Notes

Luminal A

Luminal A-likeall of:ER and PgR +HER2 -Ki-67 ‘low’

Ki-67< 14% or 20% PgR ≥20%

Luminal B

Luminal B-like (HER2 negative)ER +HER2 -and at least one of:Ki-67 ‘high’PgR ‘negative or low’

Ki-67 ≥ 14% or 20% PgR <20%

Luminal B-like (HER2 positive)ER +HER2 +Any Ki-67, Any PgR

Erb-B2 overexpression

HER2 positive (non-luminal)HER2 +ER and PgR absent

Basal-likeTriple negative (ductal)ER and PgR absentHER2 -

There is an 80% overlap between ‘triple-negative’ and ‘basal-like’ subtype. TNBC also includes some special histological types

SURROGATE DEFINITIONS OF INTRINSIC SUBTYPESSURROGATE DEFINITIONS OF INTRINSIC SUBTYPES(St Gallen International Expert Consensus 2013)

Goldhirsch A, Ann Oncol 2013

SOMATIC MUTATIONS AND MOLECULAR SOMATIC MUTATIONS AND MOLECULAR ALTERATIONSALTERATIONS

TREATMENTTREATMENT

ADJUVANT THERAPYAfter the main cancer treatment (surgery)Targets microscopic residual/metastatic diseaseIncrease the percentage of cure (prevent cancer recurrence) and improve DFS and OSAgents that are active in the metastatic setting

NEOADJUVANT THERAPYBefore the main cancer treatment (surgery)Aims to shrink a large cancer, making it easier to remove with surgeryRender resectable an unresectable locally advanced cancer, or result in less demolitive surgeryAgents that are active in the metastatic setting

PALLIATIVE THERAPYAdvanced diseaseRelieve symptoms, prolong survival, reduce complications, improve quality of life

PRIMARY BREAST CANCER SURGERY

SURGERY OF THE PRIMARY TUMORSURGERY OF THE PRIMARY TUMOR Mastectomy BCS: Lumpectomy, Quadrantectomy, Segmental Mastectomy, Partial Mastectomy

RCTs and Meta-analysis have shown:

Comparable local control and OS

Better cosmetic outcomes for BCS

MASTECTOMY VS

BREAST CONSERVING SURGERY (BCS)

BCS → DCIS, stage I-II cancer; not if multicentric disease

BCS must always be followed by adjuvant RT on the residual ipsilateral breast tissue

ADJUVANT TREATMENTS

RADIATION THERAPY (RT)(within 6 months from primary tumor surgery)

On the residual ipsilateral breast tissue if BCSOn the chest wall if T3-T4 tumorOn the ipsilateral lymph node sites if N2-N3 disease

CHEMOTHERAPY(within 2-6 weeks from primary tumor surgery)

Cyclophosphamide + Methotrexate + Fluorouracil (CMF) [d1,8 q28 6 cycles]Epirubicin (or Doxorubicin) + Cyclophosphamide (EC or AC) [q21 4-6 cycles] EC or AC [q21 4 cycles] → weekly Paclitaxel (TAX) [12 cycles] or Docetaxel (T) [q21 4 cycles]Fluorouracil + Epirubicin (or Doxorubicin) + Cyclophosphamide (FEC or FAC) [q21 6 cycles]Docetaxel + Epirubicin (or Doxorubicin) + Cyclophosphamide (TEC or TAC) [q21 4-6 cycles]

ENDOCRINE THERAPY (ET)(if ER+ and/or PgR+)

SERMs: TamoxifenAIs: Anastrozole, Letrozole, ExemestaneSurgical or chemical castration

ER expression threshold

GuidelinesGuidelines → ER status must be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by IHC

Iwamoto T, JCO 2012Yi M, Ann Oncol 2014

Relationship between ER IHC status, ESR1 mRNA expression, and ER-associated gene signature expression

OS by (A) estrogen receptor IHC status and by (B) ESR1 mRNA expression

ER-positive 1%–9% tumors have clinical and pathologic characteristics different from ER-positive ≥10% tumors. Similar to patients with ER-negative tumors, patients with ER-positive 1%–9% tumors do not

appear to benefit from ET

ER IHC: blue 0%, green 1-9%, purple 10%, gold >10%

ADJUVANT THERAPY- ENDOCRINE THERAPY -

All patients with invasive HR+ tumor (any T, any N)

If chemotherapy is administered, ET should start at the end of this

PREMENOPAUSE POSTMENOPAUSE

Tamoxifen 10 years (± ovarian suppression) AI 5 years

Tamoxifen 10 years

Tamoxifen 5 years → AI 5 years

Tamoxifen 2-3 years → AI 2-3 years

TOXICITY Tamoxifen: endometrial cancer, hot flashes and other menopausal symptoms, deep vein

thrombosis or pulmonary embolism AIs: hot flashes and other menopausal symptoms, ischemic heart disease,

osteopenia/osteoporosis, dyslipidemia

ASCO GUIDELINES 2014

DUCTAL CARCINOMA IN SITU

A) Mastectomy → 5 years Tamoxifen

B) BCS → RT and 5 years Tamoxifen

LOBULAR CARCINOMA IN SITU Uncertainty over the potential risk of evolution toward invasive cancer

MANAGEMENT: surveillance

High risk of invasive cancer evolution Frequent relapse as DCIS or invasive cancer

MANAGEMENT

ADJUVANT THERAPYINVASIVE BREAST CANCER

SURROGATE SUBTYPE TYPE OF THERAPPY NOTES

Luminal A-like Endocrine therapy

Endocrine therapy is the most critical intervention and is often used alone

Cytotoxics may be added in selected patients:- grade 3- N2-3 - age <35 years ?

Luminal B-like (HER2 negative)Endocrine therapy for all patients,

cytotoxic therapy for most

Luminal B-like (HER2 positive)Cytotoxics + anti-HER2 → endocrine

therapy

HER2 positive (non-luminal) Cytotoxics + anti-HER2

Triple negative Cytotoxics

St Gallen International Expert Consensus 2013Goldhirsch A, Ann Oncol 2013

Risk of recurrence by genomic assays: Oncotype DX, MammaPrint, Mammostrat

ADJUVANT THERAPY- TRASTUZUMAB (Herceptin) -

All patients with HER2-positive tumors ≥ T1c or N+Administer concurrently with Taxane, then complete 1 year of treatmentOUTCOMES → DFS increase of 12% at 3 years; 33% reduction in the risk of deathMonitor heart function (ECG, ejection fraction)

REGIMENREGIMEN

EC (or AC) → Taxane + H → H

FEC (or FAC) → Taxane + H → H

Docetaxel + Carboplatin + Trastuzumab (TCH) → H

Slamon D, NEJM 2011

BCIRG 006 studyNSABP trial B-31 + NCCTG trial N9831

Romond EH, NEJM 2005

NEOADJUVANT THERAPY

T3-T4 or N+ tumors; locally advanced unresectable tumor; inflammatory breast cancer

HER2-negative HER2-positive Selected HR+ patients

EC or AC → Taxane TEC or TAC FEC or FAC CMF

EC or AC → Taxane + Trastuzumab FEC or FAC → Taxane + Trastuzumab Taxane + Trastuzumab Chemotherapy + dual anti-HER2 therapy

Trastuzumab concurrently with neoadjuvant chemotherapy and continued after surgery for a total of 1 year

Endocrine therapy

Patients who attain pCR defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive subtypes.

Cortazar P, Lancet 2014

EARLY BREAST CANCER TRATMENT COMPLICATIONS- LYMPHEDEMA -

More common in patients who have undergone both axillary RT and surgery SLNB + radiation therapy → frequency 23% ALND + radiation therapy → frequency 35% in node-negative and 48% in node-positive patients

Lawenda BD, CA Cancer J Clin 2009

FOLLOW-UP

Visits every 3 to 4 months in the first 2 years, every 6 months from years 3–5 and annually thereafter

Ipsilateral (after BCS) and contralateral mammography is recommended every 1 to 2 years

In asymptomatic patients, there are no data to indicate that other laboratory or imaging tests produce a survival benefit

For patients on Tamoxifen an annual gynaecological examination is recommended

For patients on AI regular bone density evaluation is recommended

The use of hormone replacement therapy increases the risk of recurrence and should be discouraged

RELAPSE

LOCAL RELAPSELOCAL RELAPSE

Surgery ± RT → “adjuvant” therapy

First-line therapy

Before starting any therapy: Biopsy with IHC evaluation Restaging: blood analysis, chest + abdomen CT, bone scintigraphy, PET-CT

METASTATIC RELAPSEMETASTATIC RELAPSE

First-line therapy

If IHC markers are discordant between the primary tumor and the relapse

Use targeted therapy (ET and/or anti-HER2 therapy) when receptors are positive in at least one biopsy

ESO-ESMO 2nd international consensus guidelines for advanced breast cancer

Cardoso F, Ann Oncol 2014

In the first years the risk of recurrence is higher in patients with ER-negative cancers

Relapses of breast cancer may occur as late as >20 years after the initial diagnosis, particularly in patients with luminal disease

BRAIN METASTASISBRAIN METASTASIS

Specific treatment

ADVANCED DISEASE

Polychemotherapy offers no survival advantage over sequential monotherapy, and is graved by higher toxicity

ET should be offered as initial treatment in case of limited and asymptomatic visceral ER+ disease

Therapeutic decision: age, performance status, menopausal status, previous therapies, comorbidities, differential toxicities, disease extent, symptoms

In cases where a rapid tumor shrinkage is required (life threatening disease), a polychemotherapy may be preferred

In case of bone metastasis, a bone-modifying agent (BMA) must be administrated together with cancer specific treatments

ADVANCED DISEASE- HER2-NEGATIVE -

First-lineFirst-line: Endocrine Therapy (Tamoxifen, AIs, Fulvestrant) Anthracyclines Taxanes Bevacizumab + Paclitaxel Vinorelbine Carboplatin (in TNBC)

MEDIAN SURVIVAL 3 YEARS

Further linesFurther lines: Endocrine Therapy Everolimus + Exemestane Anthracyclines Taxanes Vinorelbine Eribulin Gemcitabine Capecitabine Nab-Paclitaxel Metronomic chemotherapy

ADVANCED DISEASE- HER2-POSITIVE (ASCO GUIDELINES 2014) -

First-lineFirst-line: Pertuzumab + Trastuzumab + Taxane

Second-lineSecond-line: T-DM1 Trastuzumab + chemotherapy

Trastuzumab + Lapatinib

Third-lineThird-line:: T-DM1 Trastuzumab + chemotherapyTrastuzumab + Lapatinib

Verma S, NEJM 2013Krop IE, Lancet Oncol 2014TH3RESA trial EMILIA trial

Further linesFurther lines:: Chemotherapy ± anti-HER2ET ± anti-HER2

Swain SM, Lancet Oncol 2013CLEOPATRA trial

OUTCOMES OS: 37.6 months (placebo) VS not reached (Pertuzumab)PFS: 12.4 months (placebo) VS 18.7 months (Pertuzumab)

ADVANCED DISEASE- TRASTUZUMAB EMTANSINE (T-DM1) -

ADVANCED DISEASE- EVEROLIMUS (Afinitor) -

mTOR inhibitor (mTORC1 complex)

Approved for the treatment of: Advanced HR+ breast cancer after progression with non-steroidal AIs (BOLERO-2 trial) Advanced pancreatic NETs Advanced renal cell carcinoma

Baselga J, NEJM 2012

BOLERO-2 trialBOLERO-2 trial

Andrè F, Lancet Oncol 2014

BOLERO-3 trialBOLERO-3 trialEverolimus + Trastuzumab + Vinorelbine

in Her2+ Trastuzumab-resistant mBC

METRONOMIC CHEMOTHERAPY

Andrè N, Nat Rev Clin Oncol 2014

KEY FEATURESKEY FEATURES

Frequent administration, low dose, minimal drug-free breaks

Oral administration

Minimal toxicity

Cumulative doses of a long-term metronomic therapy can be similar or even higher than those of MTD regimens

Metronomic therapy in mBCMetronomic therapy in mBCVinorelbine, Capecitabine, Cyclophosphamide, Methotrexate

Up to 80% of patients with mBC develop bone metastases

Complications: pain, disability, hypercalcemia, skeletal-related events (SREs)

skeletal-related events (SREs)

- Radiation to bone (to alleviate pain or prevent fracture)

- Pathologic fractures

- Surgery to bone (to treat or prevent fractures)

- Spinal cord compression (→ paresthesia, incontinence, paralysis)

SREs occur in up to 64% of patients with mBC (if not treated with BMAs)

BMAs effect → pain reduction, prevention of SREs, treatment of hypercalcemia

BONE METASTASISRadiography

Bone ScintigraphyCT scan

PATHOLOGIC FRACTURE

BONE-MODIFYING AGENTS- ZOLEDRONIC ACID (Zometa) -

Schedule: 1 vl 4 mg e.v. q28, for 2 years

Toxicity: hypocalcemia, nephrotoxicity, ONJ

Data on file, Novartis

BONE-MODIFYING AGENTS - DENOSUMAB (Xgeva) -

Schedule: 1 vl 120 mg s.c. q28, for 2 years

Toxicity: hypocalcemia, ONJ

Stopeck AT, JCO 2010Data on file, Amgen

OSTEONECROSIS OF THE JAW (ONJ)

Exposure of mandibular or maxillary bone through lesions in the gums that do not heal

Pain, inflammation of the surrounding soft tissue, secondary infection or drainage may or may not be present

Zoledronic Acid in the early breast cancer?

DTCs have been found in the bone marrow (BM) of patients with breast cancer and are an independent prognostic indicator of increased risk of distant disease development and death

Patients with detectable DTCs after cytotoxic chemotherapy have a high risk of recurrence Braun S, NEJM 2005

Aft R, Lancet Oncol 2010

Zoledronic acid decreases the proportion of patients with DTCs in the BM

Rack B, Anticancer Res 2010

no clinical benefit from the addition of Zoledronic acid to standard adjuvant

treatments for early breast cancer

Coleman R, Lancet Oncol 2014

CANCER CACHEXIA

Is associated with poor tolerability of cancer treatment and reduced quality of life and survival expectations

Loss of weight and muscle mass, with or without the loss of fatty mass, often associated with anorexia, inflammatory processes, insulin resistance and increased tissue protein turnover rates

CAUSES OF DEATH IN PATIENTS WITH ADVANCED BREST CANCER

Liver insufficiency

Respiratory insufficiency

Cardiocirculatory failure

Brain metastasis

Infections

Thrombosis or bleeding

Treatment complications