What the clinician needs to know about breast pathology ... · What the clinician needs to know...

What the clinician needs to know about breast pathology and sample quality

Frédérique Penault-Llorca MD, PhD

Centre Jean PERRIN – 58 Rue Montalembert - 63011 CLERMONT-FERRAND CEDEX

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Breast cancer

• Classical biomarkers

• Proliferation

• Prediction of response

• Molecular classification

• Importance of quality assurance in breast cancer

• Molecular signature

• Emerging targets5t

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Basically for the pathologist, the missions did not change….

• What is it, is benign, at risk or malignant?

• If it is at risk, which follow up ?

• If it is malignant, is it aggressive or “quiet”?

• How do I treat?

• Did I remove everything ?

To try to answer to 5 major questions

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Answers

• What is it, is benign, at risk or malignant?

• If it is at risk, which follow up ?

• If it is malignant, is it aggressive or “quiet”?

• How do I treat?

• Did I remove everything ?

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Priceless Information is Given by the Pathologist, AND will Never be Given by Molecular Testing!5t

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But we also have classical prognosis and predictive factors

• Age

• Grade

• Histological subtypes

• ER/PR and HER2 status

• Ki67 +/- mitotic index

• Vascular invasion

• Tumor margins

Oldies but

goldies

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TNM parameters:

• Pros – Treatment decisions are

based on T size

– Node involvement is a major prognosis factor

– Micrometastasis can be detected in sentinel lymph node by IHC

• Cons– TNM is decreasing

because of mass screening (69%of T1 in France in 2015)

– 70% of N0 in France in 2015

– SLN: axillary dissection is debatable in case of Nano/micromets

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Clarification of the AJCC 7th edition

Staging multiple tumors• If in same breast:

– T category is based on single largest tumor focus

– Don’t include satellite foci when measuring tumor size

– If multiple foci of microinvasion, report the # of foci and the size of the largest focus (don’t combine)

– Use (m) modifier

• If bilateral: – Stage each side separately

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Clarification of the AJCC 7th edition in the 8th edition

• Correlate gross, microscopic and imaging findings to assign correct pT when necessary.

- For small tumors diagnosed by core biopsy, measuring only the residual tumor in the excision may result in understaging. • Example:

– 6 mm mass by imaging; largest focus in biopsy core – 4 mm – 2 mm focus of residual carcinoma in excision: categorize as

pT1b (not pT1a) – No residual cancer in excision: categorize as pT1a (not pTX)

• Same rule applies when tumor is present in multiple fragments: Use clinical and imaging findings to assign pT

• pTX should rarely be used 5t

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Grade I

Grade II

Grade III8,9

SBR grade modified by Elston and Ellis

• Standardization of tumor grading

• France 2010: Gr I 25%, Gr II 50% , Gr III 25%

• Genomic grade : not confirmed

SBR grade and RFS in operable BC (57% N-) treated by adjuvant therapy

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VASCULAR EMBOLI

Lymphovascular invasion and BCSS in N-operable BC treated by adjuvant therapy (from Lee) 5t

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Group 3 - Average prognosis:Medullary, classical lobular, lobular mixed

Group 1 - Excellent prognosis: Tubular, invasive cribriform, mucinous

Group 2 - Good prognosis:Tubular mixed, mixed ductal NST and special type like adenoid cystic, secretory

Group 4 - Poor prognosisDuctal NST, solid lobular, mixed ductal NST and lobular, micropapillary

18 Histological types: morphology matters!

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Special types

« The heterogeneous « Triple negative » subtype includes adenoid cystic, juvenile secretory (good prognosis), medullary (intermediate prognosis), and metaplasic (either low grade, with good prognosis; or high grade, with poor prognosis) carcinomas, for which no generalizations can be proposed) »

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Medullary features and BCSSFrom medullary

Tubular

Non tubular

Tubular carcinoma and DFS (Rakha)

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Special types

“Tubular and cribriform carcinoma may be suitable for observation without therapy or

for endocrine therapy alone”

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Special types

“rare variant of lobular carcinoma (e.g. pleomorphic) (up to 25% HER2+) and apocrine carcinoma require treatment according to their biological features in a manner analogous to that used for ductal carcinoma “

Pleiomorphic lobular carcinoma

E CADH HER2

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Breast cancer histological types and molecular alterations

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Prediction

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Biomarker Prognostic PredictiveTechnical

validation

Clinical

validation

ER ++ +++ YES LOE Ib YES

PgR +++ ++ YES LOE Ib NO

HER2 ++ +++ YES LOE Ib YES

Ki67 ++ + NO NO

Test and scoring recommendations

IHC ≥10%

IHC ≥10% cells with complete membrane staining

ISH: number of HER2 gene copies ≥6 or the ratio HER2/chromosome

17 ≥2

IHC no final consensus on cut-off around 20%

(Ki67< 10% = low ; Ki67>30% =high)

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Ki67 why?

• Definition of luminal A and B

• Decision of CT for ER+, Grade II tumors

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Ki67 = Not standardized

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Ki67 >70%

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Ki67 >70%

Ki67<5%

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Ki67 >70%

Ki67<5%

Ki67~20%

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Ki67 15%

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Negative predictive value

(<5% chance to respond to anti-estrogens or trastuzumab)

HIGH 95%

Positive predictive value

30-50%

Breast Cancer

ER/PGR

What is the level of prediction accuracy clinically useful?

Cut off 1%

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• 240 cases• 144 high ER (>10%), 75 ER negative and 21 low-ER

(1-10%) tumors by IHC• qRT-PCR test with 6 ER related genes• ½ low-ER positive tumors ER negative group

based on the probability score• 95% of ER negative and 92% of the high ER positive

tumors classified correctly (p<0.0001). • Survival of the low-ER group was intermediate

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In case of weak ER (1-9%) in practise

• On biopsy: redo on surgical specimen

• On surgical specimen:take into account alsothe other parameters

• Role of Gene Expression Signatures (GES) ?

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INTRINSIC (MOLECULAR) CLASSIFICATION AND SURROGATE

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Towards a simplified taxonomy of breast cancer? « definition

of intrinsic subtypes has proven efficient in defining prognosis for breast cancer patients »

RE neg RE pos

C Perou & T Sorlie

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Biology of breast cancer is influenced by age

de Kruijf Mol Oncol 2014, Jenskins Oncologist 2014

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African (mean age = 45 y)

African American (premenopausal)

African American (postmenopausal)

White in US (premenopausal)

White in US (postmenopausal)

White in Poland (mean age = 56 y)

Japanese (median age = 54 y)

0% 20% 40% 60% 80% 100%

Molecular biology of BC is influenced by ethnies and country of residence

Luminal A

Luminal B

Non classées

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Molecular biology of BC influence the metastatic diffusion routes

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• ER+, HER2- EBC: Luminal A and B subtypes predict 10-

year outcome regardless of previous systemic treatment as

well as residual risk of distant recurrence after 5 years of

endocrine therapy.

• HER2+: the 4 main intrinsic subtypes can be found

• HER2+/HER2-enriched benefit the most from

neoadjuvant trastuzumab, or dual HER2 blockade with

trastuzumab/lapatinib, in combination with CT

• HER2+/Luminal A disease have a relative better

outcome compared to the other subtypes.

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• triple-negative breast cancer (TNBC), of 70-80%

Basal-like from a biological perspective, should be

considered a cancer-type by itself.

• Distinction between Basal-like versus non-Basal-

like within TNBC predict

• survival following (neo)adjvuvant multi-agent

chemotherapy,

• bevacizumab benefit in the neoadjuvant setting

(CALGB40603)

• docetaxel vs. carboplatin benefit in first-line

metastatic disease (TNT study).

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St. Gallen 2013

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Personalizing the treatment of women with early breast

cancer: highlights of the St Gallen International Expert

Consensus on the Primary Therapy of Early Breast Cancer

Luminal A all of:ER and PR positiveHER2 negativeKi-67 ‘low’Recurrence risk ‘low’ based onmulti-gene-expression assay (if available)

Luminal B ER positiveHER2 negativeand at least one of:Ki-67 ‘high’PR ‘negative or low’Recurrence risk ‘high’ based onmulti-gene-expression assay (if available)

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Personalizing the treatment of women with early breast

cancer: highlights of the St Gallen International Expert

Consensus on the Primary Therapy of Early Breast Cancer

Luminal A Endocrine therapy often used alone.Cytotoxics may be added in selected patients.

• High risk status with gene signature, if available;• Grade 3 disease;• Involvement of four or more lymph nodes;• Young age (<35 years)

Luminal B Endocrine therapy for all patientsCytotoxic therapy for most.

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Surrogate definition of intrinsic subtypes of breast cancer

«basal-like»• ER and PgR absent• HER2 negative• Approximately 80% overlap between « triple

negative » and intrinsic « basal-like »• But « triple negative » also include good

prognosis special types such as medullary and adenoid cystic carcinoma

• Staining for basal keratin is considered insufficiently reproducible for general use

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Basal-likeTriple-negative

Triple negative BC by IHC and molecular subtypes: a 80% concordance

Medullary

Adenoid cystic

Low grade squamous

Secretory carcinoma

TNBC subtypes of excellent prognosis

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Classical prognosis and predictive factors

• Age

• Grade

• Tumor margins

Oldies but

goldies

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FOCUS ON HER2 GUIDELINES

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Huge benefit from anti HER2 therapies for patients

with mBC and eBC

13-15% HER2+ in eBC18% in mBC if previously treated ~20-25 if naive

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Heterogeneity: Where to count?

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1. Simplification of IHC 2+ definition (moderate/weeak)

2. Re-testing on surgical specimen if a biopsy is HER2 - :

“may” in instead of “should”

3. Revision and/or definition of difficult ISH categories (monosomies, co-amplification, “equivocal”) avoid as much as possible “equivocal/eligible” cases

Act III?

Based on IHC results

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Messages for HER2 ASCO/CAP new guidelines

Effet magique recoHER2 2007-2018 ?

• Simplification of HER2 2+ 2• No longer systematic re-testing• Difficult ISH categories: between 4-6 copies +/- ratio

HER2/CEP17<2• Interpretation with IHC++++• Independant (second reader for ISH) for 2+• Disparition of equivocal ISH category

• Category 2 (monosomy): rather negative• Caegory 3 3 (co-ampl): rather positive• Category 4(ex-equivocal): rather negative

• Avoid single probe ISH5t

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QUALITY ASSURANCE

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Sources of variation in biomarkers testing

Time to slicing and

fixation Method of tissue

processing

Type of

fixation

Equipment

calibration

Laboratory

procedures

Time of

fixation

validation

competenceType of antigen

retrieval

reagents

Control

materials

conditions

Use of

analysis

Interpretation

criteria

Reporting

elements

Scoring

system

Wolff et al 2007

IHC, ISH

testing

variables

Post-analytical Pre-analytical

Analytical

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Interlaboratory discrepancies

All the HER2+ patients are not

inditentied for treatmentKey Insight

CHU/AP

CHG/CH

FRANCEOverexpression Rate EBC

10,8%11,0%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Avg

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Courtesy of Antonio Wolff

HER2 testing (dis)concordance in adjuvant trastuzumab trials

Concordance Central vs. Local Lab

N9831JNCI

2002(total n = 119)

2004(total n = 976)

JCO 2006(total n = 2535)

IHC 3+(HercepTest)

74% 79.5% 82%(false pos 18%)

FISH +(PathVysion)

67% 85% 88%(false pos 12%)

Magnitude of false-neg HER2 testing unclear but real…5th

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The ALTTO trial

PATIENTS 10829

NO TUMOR 244

DCIS only 297

HER-2 NOT

ELIGIBLE

1329 locally pos (14.6%)

463 locally equivocal

ELIGIBLE 8496

730 locally equivocal

(61.2%)

Courtesy G Viale

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Patients 3451

No tumor 15

DCIS only 34

Not assessable (core biopsy, etc.)

HER-2 Not eligible 338 (9.8%)

Eligible 2998

APHINITY Trial

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Quality is a multidisciplinary matter

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Specimen is viable

& biologically

reactive

Molecular composition subject to

further alteration/degradation

Factors (examples)

• Antibiotics

• Other drugs

• Type of anesthesia

• Duration of anesthesia

• Arterial clamp time

Factors (examples)

• Time at room temperature

• Temperature of the room

• Type of fixative

• Time in fixative

• Rate of freezing

• Size of aliquots

Time.0

Pre-acquisition Post-acquisition

Biospecimen lifecycle: preanalytical factors

affect molecular composition and integrity

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Rapidity of fixation

Invasive ductal carcinoma

Breast cancer

Histopronostical Annotations

Quick procedure quality of RNA but alsoof proteins

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Antigen’s degradation

→ degradation of antigens (ER, PR, HER2) after retardated fixation (from1h) and overnight à +4°C in a saline solution

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Deleterious effect of

underfixation on breast

biomarkers

Modern Pathol

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Key Recommendations: Pathologists

• Should ensure that any specimen used for HER2 testing (cytological specimens, needle biopsies, or resection specimens) begins the fixation process quickly (time to fixative within 1 hour) and is fixed in 10% neutral buffered formalin for 6 to72 hours, and that routine processing, as well as staining or probing are done according to standardized analytically validated protocols

• Should ensure that the laboratory conforms to standards set for CAP accreditation, or an equivalent accreditation authority, including initial test validation, ongoing internal quality assurance, ongoing external proficiency testing, and routine periodic performance monitoring.

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Multidisciplinary sessions

Treatment initiation Oncologist afterthe multidisciplinary tumor board

Tissue biopsy

Radiologist, endoscopist, surgeons

Sampling Fixation IHC testing

Treatment

Realization of IHC tests

Technician

Fixation and tissue transportation

Nurses , OR nurses, courier

Interpretation and pathology report

Pathologist

Diagnostic

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Possibility of vaccum preservation before fixation (tissue safe system)

Inking of the breast specimen

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Her2 testing - Internal control: normal breast

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External controls

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Overfixation is less harmfull

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TAKE HOME MESSAGES

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When to question a pathology report

• PgR+, ER-

• Lobular, tubular carcinoma HER2+

• Grade 1, ER+++, PgR+++, HER2+

• Grade 3, ER-, ki67 <5%

• Grade 3 ER+++, PgR+++

• Medulary carcinoma (carcinoma with lymphocyticinfiltrate) is extremely rare (ask for a second opinion)

Redo HER2 on surgical specimen if grade 3, ER- or ER+

If ER and/or PgR is negative on a biopsy redo on surgical specimen

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Is it a breast cancer?

• Metastasis to the breast are rare 0,2 à 1,3

• Most frequent– Lymphoma

– Melanoma

– Carcinoma (lung, GYN, kidney, digestive tract, prostate …..)

– Neuroendocrine non mammary tumors

• First clinical sign of the disease in 30% of cases

• Metastasis can occur after 10 yrs (up to 22 yrs) (melanoma, ovary…).

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Is it a breast cancer?

• Clinical presentation large nodules, growing fast, welldemarcated sometimes they are supercial.

• Can mimmick benign lesions (ACR3)

• Frequently unique

• beware of triple negative lesions with an unusual presentation (mucinous for instance)

• beware of ER+ with papillary aspects and psammomas

• aspect of lobular carcinoma in a men

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CONCLUSION

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Classical prognosis and predictive factors.

• Age

• Grade

• Ki67

• Molecular tests

• Tumor margins

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Patient with

cancer

Biospecimen

tumor « mini-me »

Researcher

Oncologist

Patient cured

Reflects tumor

biology

Personalized medicine

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Patient with

cancer

Biospecimen

tumor « mini-me »

Researcher

Induced

molecular

changes

Oncologist

Patient not cured

Reflects tumor

biology

Personalized medicine

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MOLECULAR SIGNATURES

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Yes , we have molecular biology !

• Age• Grade

• Tumor margins

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Centralized tests

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MammaPrint

(Agendia, NL)

HR+ ET HR - / HER2- , T < 5cm, N ≤ 3

Fresh frozen=> FFPEDNA array

70 GENES CELL CYCLE/ PROLIFERATION

SIGNAL TRANSDUCTION

INVASION, METASTASIS, ANGIOGENESIS

« CENTRALIZED » TEST

RECENTLY ADAPTATED TO FFPE

Group of genes (« signatures »)

EARLY RECURRENCE (Dg < 5 ans)

PROGNOSTIC GOOD SIGNATURE :

LOW RISK

POOR SIGNATURE :HIGH RISK

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OncotypeDX

(Genomic Health, USA)

HR+ / HER2- , T1-3, N-/N+

FFPE specimens

qRT-PCR

21 GENES PROLIFERATION, OESTROGENE,

HER2, INVASION (16 GENES) + REFS (5 GENES)

« CENTRALIZED » TEST

(recurrence score) RS

Late recurrence (10 years)

Benefit from adjuvant TT

PROGNOSTIC AND PREDICTIVE

LOW RISK :+ HORMONOTHERAPY / - CHEMOTHERAPY

INTERMEDIATE RISK :DISCUSSION

HIGH RISK :+ HORMONOTHERAPY / + CHEMOTHERAPY

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<26 prognosis

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Decentralized tests

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EndoPredict

(Sividon, GE)

HR+ / HER2- , T1-2, N0

FFPEqRT-PCR

8 GENES SIGNATUREPROLIFERATION, OESTROGENES

« LOCAL » TEST(SPECIAL EQUIPMENT IS REQUIRED)

SCORE OF RECURRENCE EP SCORE

LATE AND EARLY RECURRENCES

(5 & 10 YEARS)

PROGNOSIS

LOW RISK

HIGH RISK

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Prosigna (PAM50)

(NanoString Technology, USA )

IDENTIFICATION OF « MOLECULAR3 SUBTYPES »

(LumA, LumB, HER2-enrichi, Basal)

FFPEDNA ARRAY WITH BARCODES

(1 gene = 1 barcode)

50 GENES

« LOCAL » TEST (SPECIAL EQUIPMENT IS REQUIRED)

LATE AND EARLY RECURRENCES

(5 & 10 YEARS)

PROGNOSIS

LOW RISK (ROR)

Intermediate risk

HIGH RISK (ROR)5t

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Mammaprint™ Oncotype DX® Prosigna® Endopredict®Number of Genes 70 21 50 11

Method DNA-Microarray RT-PCR Nanostring RT-PCR

Sample Type Frozen/FFPE FFPE FFPE FFPE

Location Central* Central Local Local

Test Results High or low risk + SubtypeRS High/Low risk

ROR High/Intermediate/Low risk + Subtype

Calculated with T&N

EP Clin High or low riskCalculated with T&N

Clinical Indication by EGTM

Predicting prognosis and guiding decision-making

regarding chemotherapy for women with ER+/HER2- EBC

with LN- or LN+ (1-3)

Prospective Validation MINDACT (positive)TAILORx (positive)

/ RxPONDER (ongoing)OPTIMA trial (ongoing) None

Agency approval EMA, FDA EMA, FDA EMA, FDA EMA, FDA

Original Validation set

Developed in young patients (<55 years), who had not

received systemic therapy following surgery

Developed in patients who had received tamoxifen only in the NSABP B-20 and B-14

studies

Developed in postmenopausal patients,

who received ET in the TransAtac trial

Developed in postmenopausal patients,

who had received ET only in the ABCSG-6 and 8 trials

Guidelines / scientific societies that recommend the test

ASCO, EGTM, ESMO, St. Gallen Panel

ASCO, EGTM, ESMO, NCCN, St. Gallen Panel

ASCO, EGTM, ESMO, St. Gallen Panel

Paik et al. N Engl J Med. 2004, 51:2817-26; Paik J Clin Oncol 2006, 24:3726-3734; Filipits et al. Clin Cancer Res. 2011; 4. Bueno-de-Mesquita et al. Lancet Oncol. 2007;

5. Mook et al. Breast Cancer Res Treat. 2009; 6. Sapino et al. J Mol Diagn. 2013; 7. Dowsett et al. J Clin Oncol. 2013; 8. Gnant et al. Ann Oncol. 20135th

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EMERGING BIOMARKERS

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Upcoming biomarker: quantification of stromalLymphocytes (sTILs)

• Standardized (international recommendations)

• Semi-quantitative evaluation on H&E

• Predictive of NACT response in TNBC and HER2 breast cancer

• Prognostic value (primary tumor, and residual T after NACT)

• Predictive for immunotherapy?

Salgado et al Annals of Oncol,2015

Loi et al Annals of Oncol 2014

Dieci et al Sem Can Biol 2017

Hendry et al Adv Anal Pathol 2017

Standardized, St Gallen 2019, but clinical validityto prove5t

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Somatic BRCA status

PD-L1 Immune cells

BRCA status PARPi

PIK3CA mutations

PIK3Ci

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CONCLUSION …

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Classical prognosis and predictive factors

• Age

• Grade

• Tumor margins

Molecular signatures

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Luminal A Luminal B Triple-negative

ER<10%

PR<10%

Ki67 >14%

High grade

ER >10%

Ki67 >14%

PR < 20%

HER2 + possible

ER > 10%

Ki67<14%

PR > 20%

HER2 -

ER <10%

PR < 10%

HER2 3+

ER+ ER-

EGFR+/-

HER2 +/-

Molecular

apocrine

Tubular

Cribriform,

IDC grade 1,

Mucinous

ILC grade 1

Micropapillary

ILC grade 2 & 3

IDC grade 2 et3,

Mucinous type B

NeuroendocrineApocrine

CCI grade 3

Medullairy

metaplastic

CCI &CLI grade 3

Proliferation

Mutations of TP53 or PIK3CA

Genomic instability

Intratumor heterogeneity

BRCAness

Breast Cancer classification in practice

- Low frequency of mutations

- Mutation in numerous genes

- Most frequently mutated genes:

PIK3CA, MAP3K1, MAP2K4

CCI grade 2 & 3,

Micropapillaire

Cheang et al CCR 2008, Prat et al JCO 2013, Kennecke et al JCO 2010,

Cheang et al, JNCI 2009, Goldhirsh et al Annals of Oncol 2012 , Cirqueira et al Breast J 2015

Blows et al Plos Medicine 2010

Adenoid

cystic

Secretory

Low grade

metaplasic

ER<10%

PR<10%

Low grade

Translocations

(ETV6; NTRK3)

(MYB; NF1B)

IDH2 Mutations5t

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• ER+, HER2- EBC: Luminal A and B subtypes predict 10-

year outcome regardless of previous systemic treatment as

well as residual risk of distant recurrence after 5 years of

endocrine therapy.

• HER2+: the 4 main intrinsic subtypes can be found

• HER2+/HER2-enriched benefit the most from

neoadjuvant trastuzumab, or dual HER2 blockade with

trastuzumab/lapatinib, in combination with CT

• HER2+/Luminal A disease have a relative better

outcome compared to the other subtypes.

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• triple-negative breast cancer (TNBC), of 70-80%

Basal-like from a biological perspective, should be

considered a cancer-type by itself.

• Distinction between Basal-like versus non-Basal-

like within TNBC predict

• survival following (neo)adjvuvant multi-agent

chemotherapy,

• bevacizumab benefit in the neoadjuvant setting

(CALGB40603)

• docetaxel vs. carboplatin benefit in first-line

metastatic disease (TNT study).

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What the clinician needs to know about breast pathology ... · What the clinician needs to know...

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