Molecular Testing for Breast Cancershoustonpathologists.org/Zhang - HSCP 2016 Advocate.pdf ·...

57th HSCP Advocate Seminar 4/16/2016

Hong (Amy) Zhang, MD 1

Molecular Testing for Breast Cancers

Hong (Amy) ZhangThe University of

Texas- M D Anderson Cancer Center

4/2016

THE PAST

The “One-Size-Fits-All”Approach to Breast Cancer

Breast Cancer is a heterogeneous disease

Perou, Nature 2000;406:747-752.Perou, The Oncologist 2010.



TODAYThe “One‐Size‐Fits‐All” Approach to

Breast Cancer

“The only thing all breast cancers share in common is the organ in which the arise !!”

Breast Cancers

• Morphologically and biologically heterogeneous groups of disease

• Clinical course varies significantly

Therapy Decisions

• What type of surgery should be performed?

• Is radiation necessary?• Should and what additional

systemic neoadjuvant/adjuvant therapy be used?



Goal: Personalized Medicine

?

Cancer Diagnosis & Treatment• The biology of your breast cancer is

unique. Identifying the most effective, tailored therapies for your tumor is called Personalized Medicine

Likelihood of recurrence

Side effects of therapy

Benefits of therapy

Biomarkers/molecular testing

• These markers are substances or abnormalities that can be detected in the tumor tissue

• To predict prognosis • To guide treatment recommendations



Clinicopathological Tumor Markers

• Age• Tumor size • Tumor grade• Lymph node involvement• Metastasis

Grade 1 Grade 2 Grade 3

Biomarkers/molecular testing• Hormone receptor status (Estrogen receptor

• Progesterone receptor)• IHC (immunohistochemistry) test• positive or negative• Semi-quantitative reporting (Allred score)

• HER2/neu stands for human epidermal growth factor receptor 2– IHC (immunohistochemistry) test

• Positive, negative or equivocal – FISH (Fluorescence In Situ Hybridization) test

• Positive, negative or equivocal • Ki-67: a proliferation indicator

Major concerns…• Histological grade

– Poor reproducibility (NSABP B14)– Overall concordance 43%– G1: 36% G2: 23% G3 61%

• Ki67

Paik et al N Engl J Med 2004Dowsett et al J Natl Inst 2011



Biomarkers/molecular testing• Multi-gene testing

– OncoType Dx Test– MammaPrint Test– Prosigna– ….

• Ancillary tests to management for breast cancers with early stage post local regional treatment – Hormonal therapy alone versus active

treatment

Gene/protein prognostic signatures

Add additional information to current clinical and pathological parameters for decision making for SOME patients

Oncotype DX RS

H/I + MGI

Mammaprint

GGI

PAM50

Mammostrat

Oncotype DX 21 Gene Recurrence Score (RS) Assay

• Oncotype DX is a successful example of multigene prognostic and predictive assay performed on primary FFPE tumor samples.

• The Oncotype DX assay was initially designed to quantify the residual risk of 10-year risk of distance recurrence in patients with ER–positive and lymph node negative tumors receiving tamoxifen.

• Also used for DCIS (ductal carcinoma in situ)

(Goldstein et al, JCO 26, 2008)




• Only performed in the licensed Genomic Health laboratory where the assay was developed.

• All histologic slides (also known as H&E's) are reviewed by board certified surgical pathologists and the DCIS tumor is marked for manual microdissection.

• The dissected, enriched tumor sample then undergoes RNA extraction.

• Next, the RNA is analyzed using a technique called real-time RT-PCR (reverse transcriptase-polymerase chain reaction).

• Finally, the Recurrence Score (RS) result is calculated from the gene expression results.

• Cost: $4620 (full cost)

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENERPR

Bcl2SCUBE2

INVASIONStromelysin 3Cathepsin L2

HER2GRB7HER2

BAG1GSTM1

REFERENCEBeta-actinGAPDHRPLPO

GUSTFRC

CD68

16 Cancer genes and 5 Reference Genes

Category RS (0 – 100)Low risk RS < 18

Int risk RS ≥ 18 and < 31

High risk RS ≥ 31


Oncotype DX 21 Gene AssayRecurrence Score (RS)

• A low RS score is predictive of tamoxifen benefit in ER-positive patients

• A high RS is predictive of chemotherapy benefit over hormonal therapy in ER-positive patients, regardless of lymph node status.



338 pts149 pts181 pts

DRFS—Low, Intermediate, High RS Groups

Paik S, et al. New Eng J Med 2004

• Design: Prospective analysis of archived tissue from 668 stage I or II patients with estrogen receptor (ER)–positive, node-negative, invasive breast cancer treated with tamoxifen

• Results: Ten year distant recurrence rate was significantly lower for patients with low RS compared to those with HS

Oncotype DX 21 Gene Assay – NSABP B-14 trial

Paik et al. J Clin Oncol. 2006.

• Design: Prospective analysis of archived tissue from 651 patients with ER-positive, node-negative, invasive breast cancer with tamoxifen or Tamoxifen plus CMF/MF

• Results: • Low resurrence score

predicted little to no benefit from chemotherapy;

• High recurrence score predicted large benefit from chemotherapy;

Oncotype DX 21 Gene Assay – NSABP B-20 trial

NCCN guideline for breast cancer

For patients with ER positive/Her2 negative pT1-2 tumor:

• Low RS (<18): adjuvant endocrine therapy• Intermediate RS (18-30): adjuvant

endocrine therapy with or without adjuvant chemotherapy

• High RS (>30): adjuvant endocrine therapy plus adjuvant chemotherapy



Oncotype DX DCIS Score™

• To support personalized treatment planning for patients with DCIS following local excision treated by local excision, with or without tamoxifen

• To provide an individualized estimate of the 10-year risk of local recurrence

• Validated in ECOG E5194, a large, independent, multicenter clinical trial

Solin et al. J Natl Cancer Inst. 2013.




Solin et al. J Natl Cancer Inst. 2013.

• No Two Patients - and No Two Tumors - Are the Same

• Even patients with similar clinical and pathologic features do not all have the same recurrence risk1-3


• Integration of the DCIS Score Result Changed Treatment Recommendations 31% of the Time

Alvarado et al. ASCO 2014

MammaPrint 70-gene prognostic signature

• The MammaPrint assay was the first fully commercialized microarray-based multigene assay for breast cancer developed from the Netherlands Cancer Institute and provided by Agendia BV, Amsterdam

• 70-gene profile was FDA approved in 2007• A fresh tissue based genomics test

– Using the latest microarray technology to analyze a patient’s breast tumor biology to predict whether existing cancer has the ability to metastasize

• Currently as a pure prognostic assay for women with either ER-positive or ER-negative, lymph node–negative breast cancer.

• Out-of-pocket cost: $500• Turn around time: ~10 business days




• Indication:– Breast Cancer Stage 1 or Stage 2– Invasive carcinoma (infiltrating carcinoma)– Tumor size ≤5.0 cm– Lymph node negative– Estrogen receptor positive (ER+) or Estrogen

receptor negative (ER-)– HER2/neu: negative or positive– Women of all ages


• The 70 genes are primarily associated with proliferation, additionally associated with invasion, metastasis, stromal integrity and angiogenesis

• Based on the 70-gene signature, the patient can be assigned as good or poor prognosis profile which was found to have a strong independent predictor of the likelihood of distant metastasis.

• It requires either fresh-frozen tumor samples or tissues collected into an RNA preservative solution, which might limit its practical clinical usage in community based oncology practice.


Without adjuvant treatment at 10 years,• Low Risk: 10% chance of

recurrence; No statistical benefit from chemotherapy

• High Risk: 29% chance of recurrence; statistically benefit from chemotherapy



Prosigna Breast Cancer Prognostic Gene Signature by NanoString Technology

• NanoString nCounter® Dx Analysis System using FFPE breast tumor tissue previously diagnosed as invasive breast carcinoma

• PAM50 based breast cancer genomic signature• FDA approved RT- PCR based test• The gene expression profile of a patient’s tumor is

compared with each of the 4 PAM50 prototypical molecular profiles to determine the degree of similarity.

• PAM50 gene signature in combination with a proliferation score and tumor size an individualized Prosigna Score

• The Prosigna Score is a numerical value on a 0-to-100 scale that correlates with the probability of distant recurrence within 10 years

Ann Oncol. 2014;25(2):339-345

Prosigna Breast Cancer Prognostic Gene Signature by NanoString

• Indicated: postmenopausal women with hormone receptor-positive, node-negative (Stage I or II), or node-positive (Stage II) breast cancer to be treated with adjuvant endocrine therapy.

• Analytical and clinical validated (ABCSG-8 trail)• Report available as short as 3 business days

BMC Cancer. 2014Ann Oncol. 2014;25(2):339-345



Prosigna Breast Cancer Prognostic Gene Signature by NanoString

• NanoString nCounter® Dx Analysis System based test; it could be performed in individual labs

Next Generation Sequencing (NGS)and its clinical indication

• NGS detects mutations, deletions, translocation, amplifications, etc

• Hot spot detection mainly• Mainly indicated for patients with advanced diseases,

distant metastatic diseases and failed other treatment modalities

• For selection to potential clinical trials using novel therapeutic agents, such as novel kinase inhibitors, cell cycle modulators, or immune modulators, etc.

• Examples: BRACA1/2, EGFR mutations, P53 mutations, etc.

• Multplex panel testing also available• Require validation of clinical usage of such information



Adjuvant!Online• To help physicians make estimates of probable benefit derived by giving

adjuvant therapy to individual cancer patients; • For both practical and educational purposes.



Thank you!

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