Management of Early Breast Cancer (by Dr. Akhil Kapoor)

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rMANAGEMENT OF EARLY BREAST CANCER

Dr. Akhil KapoorDepartment of Radiation OncologyAcharya Tulsi Regional Cancer Treatment & Research Institute, Bikaner

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STAGING

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PATHOLOGIC N STAGE

pN1mi = Micrometastasis ≤ 2mm size (0.2-2mm)

or, <200 cells

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STAGES INCLUDED IN EARLY BREAST CANCER

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Multicentric in 90% of specimens Bilateral in 35-59% cases 10% Invasive ca has associated LCIS.

Must at diagnosis: Bilateral Mammogram Pathology Review

Importance of Mammogram: LCIS: A marker for increased risk for

subsequent development of invasive (usually ductal carcinoma)

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Surgical Excision Biopsy is must to proceed for management.

Management is done according to associated DCIS or Invasive Ca disregarding the presence of LCIS.

If margins are positive for LCIS, additional surgery to obtain clear margins for LCIS is not required.

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LCIS AS SOLE HISTOLOGIC DX

Most widely accepted approach: Close observation with mammographic surveillance

Patients with highest risk (Young; diffuse high grade lesion; Family history):

Bilateral Prophylactic Mastectomy

Tamoxifen alone reduces the risk by 56%.

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PAGET’S DISEASE

Rare entity: <5% of all Breast Ca cases; In fifth-sixth decade.

D/d: Eczema (B/L in Eczema) Palpable mass present in 50% cases

(Invasive Ca in 90%).

If no palpable mass, 66-86% underlying DCIS.

Prognosis and management according to underlying disease.

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USUAL MANAGEMENT:

Complete excision of Nipple Areola Complex with microscopically clear margins for both Paget’s and associated malignancy.

Followed by: Whole Breast RT

5 Year Local Recurrence Rate of 5.2% (EORTC Study)

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Pure DCIS: No indication of Axillary dissection.

Apparent pure DCIS: Upto 25% cases turn out to be Invasive Ca in lumpectomy specimen.

Thus, if Mastectomy is performed: SLNB preferred.

If lumpectomy includes Axillary tail, SLNB preferred (as surgery compromises future SLNB in the rare event of associated Invasive Ca)

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RECURRENCE

Recurrence is 50% DCIS and 50% Invasive Ca.

Risk Factors for Recurrence:1) Age <50yrs2) Palpable mass3) Close (<1mm) or involved margins4) High Grade5) Diameter >1cm6) Presence of Comedo Necrosis.

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VAN NUYS INDEX

Modified VNPI includes AGE as well.

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Whole Breast RT following lumpectomy reduces the recurrence rate by 50% in DCIS.

Boost to tumor bed by 10 Gy is recommended in cases with close margins and age <50yrs.

MRI may be advised in patients suspected to have multi centric disease.

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Patients without any high risk feature: Surgical Excision alone is sufficient.

Tamoxifen addition for 5 years (NSABP B-24 trial):

Reduces the recurrence rate by 3.4% (HR 0.30, p<0.001) in ipsilateral IBTR.

Absolute reduction in Contra lateral Breast Ca by 3.2% (HR 0.68, p=0.02).

Thus, Tamoxifen is added in ER+ DCIS after Lumpectomy and Radiation.

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Her 2 status in pure DCIS: No significance.

Indications of Simple Mastectomy in DCIS: Multicentric Disease Diffuse Microcalcifications Family History

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WORK UP FOR EARLY BREAST CA

Hematological Tests Baseline CBC, RFT, LFT(as Surgery and Chemotherapy are to be

given)

Serum Alkaline phosphatase: Raised in patients with Bone Mets

"bone burns, liver lasts" : Heat Unstable ALP in Bone diseases.

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PATHOLOGY

Pathology Review

Determination of ER, PR and Her-2-neu Status

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IMAGING STUDIES

o Bilateral Mammogram ± USG

o Bone Scan: Indicated in Localised bone pain Elevated ALP

o Chest CT: If pulmonary symptoms

o Baseline Echo/ MUGA Scan (MultiGated Acquistion- Tc99m)

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ABDOMINAL ± PELVIC CT:

Indications: Abnormal Physical Examination of abdomen

or pelvis Abdominal Symptoms Abnormal LFT Raised ALP

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BREAST MRI

Requirements: Expert Breast Imaging Team Dedicated Breast Coils Facility for MRI guided Needle Sampling or wire

localisation of MRI detected abnormalities.

Indications: To evaluate dense breasts (young) Breast Ca in Pregnancy In patients with Positive Axilla with Occult primary

(not identified with Mammogram). To determine Multicentric Disease in I/L Breast Screening of C/L Breast in high risk patients

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PET-CT

Not usually indicated. Indicated in situations when standard

imaging is equivocal/suspicious especially in locally advanced/metastatic breast cancer.

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FOR T3N1MO

Usually Part of the Initial Work up: Chest CT Abdominal CT Bone Scan

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(in absence of Extensive Intraductal Component-Boost Required)

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PRE OPERATIVE SYSTEMIC THERAPY

Indicated if patient desires BCS and fulfills the criteria for BCS except for size.

Core Biopsy with placement of image-detectable marker to demarcate the tumor bed for post-CT surgical management.

Clinically negative axilla should be checked by USG, suspicious nodes should be sampled by FNAC or core needle and clipped with image detectable marker.

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Similarly, clinically positive nodes must be sampled and clipped.

Clipped Nodes that are positive on histology must be removed at the time of Surgery.

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CT regimes are similar in neo-adjuvant and adjuvant settings.

Endocrine therapy alone may be considered in Post-menopausal patients with receptor positive disease (Aromatase inhibitor).

Her-2 + disease treated with systemic therapy along with at least 9 weeks of trastuzumab.

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DEFINITION OF MENOPAUSE

PM Range: FSH >25 IU/l; E2 <200pmol/l

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HER 2 NEGATIVE

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HER 2 NEGATIVE

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HER 2 POSITIVE

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MOA PERTUZUMAB PERJETA targets a different domain on the

HER2 receptor than trastuzumab, allowing the combination to provide a more comprehensive blockade of HER2-driven signaling pathways.

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PERTUZUMAB

The pCR rates were 39.3% in patients who received pertuzumab plus trastuzumab and docetaxel

and 21.5 % in patients who received trastuzumab plus docetaxel.

(adjusted p-value = 0.0063). The pCR rates and magnitude of

improvement with the addition of pertuzumab were lower in the subgroup of patients with hormone receptor-positive tumors compared to patients with hormone receptor-negative tumors.

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PREOP SYSTEMIC THERAPY

Confirmed Progressive disease anytime: Proceed to MRM

If CR/PR with possible BCS: Proceed to Lumpectomy

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BASELINE DOCUMENTATION OF “TARGET” AND “NON-TARGET” LESIONS

All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline.

Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically).

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A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response.

All other lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up.

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EVALUATION OF TARGET LESIONS

Complete Response (CR): Disappearance of all target lesions

Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions

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EVALUATION OF NON-TARGET LESIONS

Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level

Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits

Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions

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BCS WITH SURGICAL AXILLARY STAGING

No Axillary Node: RT to Whole Breast ± Boost APBI in selected patients

+ve Axillary Node: RT to whole breast ± Boost

+ Nodal RT ± IMN RT

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TUMOR BED BOOST

Rationale: 65%-80% of breast recurrences after BCS + RT occur around the primary tumor site.

Clark et al. noted in 1,504 patients a greater incidence of failures at 10 years of 17% in those to whom no boost was delivered, compared with 11% in those who received doses of 5 to 15 Gy at the primary excision site (P = .03)

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Currently, most institutions prefer electron beam boost because

of its relative ease in setup, outpatient setting, lower cost, decreased time demands on the physician, and excellent results compared with 192Ir

implants.

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EORTC TRIAL

Bartelink et al. after BCS and axillary dissection, stage I or II, received 50 Gy of radiation to the whole breast in 2-Gy fractions over a 5-week period

Randomly assigned to receive either no further local treatment (2,657 patients) or a boost of 16 Gy, usually given in 8 fractions by electron beam (2,661 patients).

The 5-year actuarial rates of local recurrence were 7.3% and 4.3%, respectively (P <.001).

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INTERNATIONAL BREAST CANCER STUDY GROUP TRIALS

Premenopausal with 1-3+LN: LRR 19-27% if

G2-3 disease with vascular invasion but that risk was <15% if they had G1

disease with no vascular invasion. Postmenopausal with 1-3+LN: G3 disease and T>2 cm LRR 24% as compared with <15% for those with G1–2

disease with T<2 cm.

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DOSE OF RADIATION

Dose of 45-50Gy at 1.8-2Gy per fraction given 5 fractions per week.

Another dose schedule: 42.5 Gy at 2.66Gy per fraction in 16 fractions

Boost to tumor bed in patients at high risk (Age<50 years, high grade disease) with 10-16Gy at 2 Gy per fraction.

Dose to regional nodes: 50-50.4Gy at 1.8-2Gy per fraction (±Scar Boost to 60Gy at 2Gy per fraction).

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HYPOFRACTIONATION IN BREAST

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START TRIAL A

Criteria: Early breast cancer (pT1-3, pN0-1 M0); BCS or Mastectomy

50 Gy in 25 fractions over 5 weeks 41.6 Gy/3.2Gy per fraction in 13 fractions

over 5 weeks, or 39 Gy/3Gy per fraction in 13 fractions over 5

The overall treatment time was kept constant in all three arms

Allowed treatment of regional lymph nodes (supraclavicular and axillary), used in 20%.

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RESULTS

Median follow-up was 9·3 years.

10-year rates of local-regional relapse: 50 Gy: 7.4% 41.6 Gy: 6.3% (p=0.65) 39 Gy: 8.8% (p=0.41)

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START TRIAL B

Criteria: Early breast cancer (pT1-3, pN0-1 M0)

50 Gy/2 Gy per fraction, 25 fractions over 5 wks,

40 Gy/2.67 Gy per fraction,15 fractions over 3 wks.

Results: 10-year rates of local-regional relapse: 50 Gy: 5.5% 40 Gy: 4.3% (p=0.21)

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COSMESIS

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COSMESIS

Breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the Hypofractionated group than in the 50 Gy group.

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DFS IN START A & B

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SUBGROUP ANALYSIS

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Inclusion Criteria:Invasive Breast Ca, BCS, Margins clear, N0 Control group: 50.0 Gy in 25 fractions over a

period of 35 days Hypofractionated group: 42.5 Gy in 16

fractions over a period of 22 days.

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No Nodal radiation; No Boost

RESULTSThe risk of local recurrence at 10 years: 6.7% standard irradiation 6.2% hypofractionated regimen

Good or excellent cosmetic outcome at 10 years:

71.3% in control group 69.8% in hypofractionated

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HAZARD RATIO FOR SUBGROUPS

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SELECTION CRITERIA FOR APBI (ASTRO)

Age>60 yrs pT1N0, ER + Margins Negative by at least 2mm BRCA 1, 2 Negative LVSI Absent DCIS Absent Ext Intraductal Component Absent Unicentric Unifocal (same quadrant) Histology: IDC/Mucinous/Tubular/Colloid No previous NACT Asso. LCIS allowed

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DOSE IN APBI

34Gy/3.4Gy per fraction/2 fractions per day 6 hrs apart for 5 days

For APBI by EBRT, 38.5Gy/3.85Gy per fraction/2 fractions per

day 6 hrs apart for 5 days

FOLLOWING TOTAL MASTECTOMY

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The finding comes from a meta-analysis of individual data for a total of 8135 women participating in clinical trials who were followed for an average of 11 years; 1314 of these women were found to have 1 to 3 positive nodes.

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EBCTCG STUDY

In women who had 1-3+ nodes, PMRT reduced the RR by 32% and reduced the breast cancer mortality rate by 20%.

The benefit was similar whether women had only 1+ node or whether they had 2 or 3+ nodes.

For women with ≥4 + nodes (n = 1772), RT reduced overall recurrence by 21% and breast cancer mortality by 13%.

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Woodward et al. found that the risk of LRR after mastectomy and anthracycline-based chemotherapy was only 13% for patients with stage II disease and one to three positive lymph nodes.

However, at the same institution, patients with similarly staged disease treated with PMRT had a LRR risk of only 3%.

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COFACTORS FOR >15% LRR AFTER MASTECTOMY + CT WITH 1-3 +LN

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CLINICAL CASE

A 40 year lady with lump in upper outer quadrant of breast underwent MRM with final HPR as follows: pT1N0 (T=0.4 cm), Metaplastic histology, ER+, PR-, Her 2+; other parameters favorable.

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QUESTION

What next in management?

Ans: Adjuvant endocrine therapy is sufficient.

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DECISION CHART

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QUESTION

What if the same patient was ER, PR Negative?

Ans: No adjuvant therapy

DECISION TREE

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CLINICAL CASE

A 40 year lady with lump in upper outer quadrant of breast underwent MRM with final HPR as follows: pT1N0 (T=1 cm), Ductal histology, ER+, PR-, Her 2-; other parameters favorable.

Ques: Next Management?

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ONCOTYPE DX

Analyzes a panel of 21 genes within a tumor to determine a Recurrence Score.

The RS is a number between 0 and 100 that corresponds to a specific likelihood of breast cancer recurrence within 10 years of the initial diagnosis.

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GENES ANALYZED IN ONCOTYPE DX

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Oncotype DX demonstrated both

Prognostic significance (the capability of predicting distant recurrence)

Predictive significance (the capability of the test to assess the potential benefit of additional adjuvant chemotherapy).

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Kaplan-Meier plots for distant recurrence comparing treatment with tamoxifen (Tam) alone versus treatment with tamoxifen plus chemotherapy (Tam + chemo).

Paik S et al. JCO 2006;24:3726-3734

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Relative and absolute risks of chemotherapy (chemo) benefit as a function of recurrence score (RS) risk category.

Paik S et al. JCO 2006;24:3726-3734

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CLINICAL CASE

A 40 year lady with lump in upper outer quadrant of breast underwent MRM with final HPR as follows: pT1N0 (T=0.8 cm), Mucinous histology, ER+, PR-, other parameters favorable.

Next Management?

Ans: No adjuvant therapy

DECISION TREE

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FOLLOW UP

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THANKS

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