Question 1 A. ER-, PR-, HER+ B. ER+, PR+, HER2- C. ER-, PR+, HER2- D. ER-, PR-, HER2- E. ER-, PR+, HER2+

Transcription

1 Triple Negative Breast Cancer Laura C. Collins, M.D. Department of Pathology Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA Question 1 The tumor depicted on the next slide is from a 42 year old woman with a BRCA1 germline mutation. The biomarker profile that would most likely be seen in this tumor is: A. ER-, PR-, HER+ B. ER+, PR+, HER2- C. ER-, PR+, HER2- D. ER-, PR-, HER2- E. ER-, PR+, HER2+ Question 1 Question 2 A 37 year old woman underwent an excisional biopsy for a palpable breast mass. The histologic features of the tumor are illustrated on the next two slides. Which of the following is false regarding tumors of this type? a) Tumors with these features are typically negative for ER, PR and HER2 ( triple negative ) b) Tumors with these features are commonly associated with germline BRCA1 mutations c) Tumors with these features may express EGFR d) Tumors with these features are associated with an excellent prognosis e) Tumors with these features are particularly common in African-American women 1

2 Question 2 Question 2 Question 3 Which of the following is true regarding basal-like breast cancers? a) They are usually low grade invasive ductal carcinomas b) They typically present in older women c) They commonly express basal cytokeratins such as CK5/6 d) They rarely show foci of necrosis e) They typically have an extensive associated component of DCIS It is no longer tenable to consider breast cancer as a single disease Goldhirsch, Ann Onc,

3 Breast Cancer Subtypes Determined by Gene Expression Profiling Sorlie, 2001 What is Basal-Like Carcinoma? Subtype of invasive breast cancer identified through gene expression profiling studies Express genes characteristic of basal epithelial cells Comprise ~ 15% of invasive breast cancers ER- ER+ Sorlie, 2001 Basal-like cancers as defined by expression profiling: Poor prognosis Often seen in women with BRCA 1 mutations Prognosis in Basal-like Cancers Foulkes, BCRT, 2008 While these tumors have a poor prognosis Size does not seem to predict for lymph node status (disobey sizenode rule) Size is not a reliable predictor of survival Small, node negative BLBC have an unexpectedly poor prognosis Sorlie,

4 Immunophenotype ER, PR, HER2 negative ( triple negative ) Basal cytokeratin positive CK 5/6, CK 14, CK 17 EGFR positive c-kit (CD117) positive Vimentin positive However, not an immunophenotypically homogeneous group Nielsen 2004, Clin Cancer Research, Makretsov 2004, Clin Cancer Research Livasy 2005, Mod Pathol Nielsen 2004, Clin Cancer Research Immunophenotype Nielsen, 2004 CK5/6 Panel of 4 Abs can accurately identify basal-like cancers (ER, HER2, EGFR, CK5/6) ER and HER2 negative and EGFR and/or CK5/6 positive Basal-Like Cancer 4

5 Histology of Basal-Like Cancers Identified By Expression Profiling Livasy, Mod Pathol, 2005 Histologic grade 3 (100%) Solid architecture No tubule formation, high density of cells with no intervening stroma Pushing border (61%) Stromal lymphocytic infiltrate (56%) High mitotic rate (100%) Geographic zones of necrosis (74%) Medullary-like features (Central fibrotic/acellular zone) (Little or no associated DCIS) Livasy 2005, Mod Pathol 5

6 Diagnosis Infiltrating ductal carcinoma, histologic grade 3 Biomarkers ER negative Triple PR negative Negative HER2 negative Infiltrating ductal carcinoma, grade 3 Geographic necrosis Triple Negative Is this a basal-like breast cancer? 6

7 Ki67 7

8 Did We Know About Basal-Like Cancers in the Pre-Expression Profiling Era? Poorly differentiated invasive ductal carcinomas with central acellular fibrotic zone/fibrotic focus/deposition of collagen myoepithelial immunophenotype Refining the Categorization of Basal-like Cancers While basal-like cancers as determined by expression profiling are typically ER/PR/HER2 negative (triple negative), not all triple negative cancers look alike Poor prognosis Tsuda 1999, Hum Pathol Hasebe 1997, Jpn J Cancer Research Jimenez 2001, Am J Surg Pathol Invasive Ductal Histologic Features of Basal-Like Cancers Medullary Adenoid Cystic Metaplastic What is a Basal-Like Cancer In May 2012?? BLC by expression profiling? Triple negative by IHC +/- basal CK, EGFR and c-kit? IDC with geographic necrosis or fibrotic focus? IDC with myoepithelial differentiation????? IDC with basal CK expression by IHC? BRCA-1 related carcinoma? Medullary carcinoma? Adenoid cystic carcinoma 8

9 Are They Basal-Like? Refining the Categorization of Basal-like Cancers While basal-like cancers as determined by expression profiling are most often ER/PR/HER2 negative (triple negative), not all triple negative cancers are basallike by expression profiling Weigelt, J Pathol, 2008 TRIPLE NEGATIVE BASAL- LIKE BASAL- LIKE TRIPLE NEGATIVE ~70-80% 9

10 Prognosis of Basal-like Cancers Clin Cancer Res 2009 Among 232 triple negative breast cancers, 71% showed expression of at least one basal CK (5/6, 14, 17) and/or EGFR Distinctive features of basal-like cancers Lower prevalence of LN mets More frequent marked cellular pleomorphism More often showed increased expression of certain cell cycle regulators and proliferation markers (p53, p16, c-myc, phospho-histone H3) More frequent mets to brain and lungs Worse prognosis Initial gene expression profiling studies indicated poor prognosis Some tumors that cluster in the basal-like group are characterized by a highly favorable prognosis (e.g., adenoid cystic carcinomas) Prognosis of other basal-like cancers heterogeneous Survival and Extent of Basal Cytokeratin Expression Fulford, 2007 Clin Cancer Res 2009 Diffuse basal (n=24) Focal basal (n=64) Non-basal (n=355) 10

11 Clin Cancer Res, 2007 Refining the Categorization of Basal-like Cancers Hennessy, Cancer Research, 2009 Prat, Breast Cancer Research, 2010 Metaplastic breast carcinomas are molecularly distinct group Most closely related to claudin-low subgroup Claudin-low group characterized by loss of a group of genes encoding cell-cell adhesion Also express high levels of stem cell markers Histologically spindloid morphology LMWK and ER related genes Markers of EMT (inc claudin) Markers of stem cell related genes Claudin-Low Breast Cancer: A Novel Subtype Associated with BLC and Metaplastic Carcinoma Lu, USCAP, grade 3 carcinomas (97 BLC and 18 metaplastic carcinomas) Evaluated claudins 1,3,4,7 and 8 by IHC 15% of cohort was claudin-low Majority were BLC (72% vs. 11% luminal) Within BLC, 78% of claudin-low were metaplastic vs. 15% non-metaplastic Strongly assoc. with disease recurrence Prat BCR,

12 DCIS with a Basal-Like Phenotype Bryan, Mod Pathol, 2006 Is there an identifiable precursor lesion to invasive basal-like breast cancer? 66 cases of HG DCIS 4 cases triple negative (6%) Basal CK or EGFR expressed by all 4 triple negative cases (100%) compared with only 42% of non-triple negative cases (p=0.04)? Precursor lesion to invasive basallike carcinoma DCIS with a Basal-Like Phenotype Livasy, Hum Pathol, cases of DCIS 20 cases of basal-like DCIS (7%) Higher frequency of comedo histology? Precursor lesion to invasive basal-like carcinoma Devine, USCAP, A 27 of 41 (66%) cases of TN DCIS had basal-like phenotype High frequency of comedo and solid histology with prominent inflammation Increased frequency of p16 and Cox2 expression among basal like DCIS CK5/6 12

13 Practical Considerations ER, PR, HER2 negative Practical Considerations Do you make or suggest a diagnosis of basal-like carcinoma? Do you do basal cytokeratin and/or EGFR stains on triple negative breast cancers? What do the clinicians really want to know? Does this have implications for BRCA1 testing? Practical Considerations Do you make or suggest a diagnosis of basal-like carcinoma? Do you do basal cytokeratin and/or EGFR stains on triple negative breast cancers? What do the clinicians really want to know? Does this have implications for BRCA1 testing? NO Practical Considerations Do you make or suggest a diagnosis of basal-like carcinoma? Do you do basal cytokeratin and/or EGFR stains on triple negative breast cancers? What do the clinicians really want to know? Does this have implications for BRCA1 testing? 13

14 What Do the Clinicians Want to Know (as of May 2012)? ER, PR, HER2 status drives therapeutic decision making If triple negative Poor prognosis Not candidates for hormonal therapy Not candidates trastuzumab? Platinum-based chemotherapy? Targeted therapies with EGFR or PARP inhibitors Practical Considerations Do you make or suggest a diagnosis of basal-like carcinoma? Do you do basal cytokeratin and/or EGFR stains on triple negative breast cancers? What do the clinicians really want to know? Does this have implications for BRCA1 testing? Does This Have Implications for BRCA1 Testing? Given that Most triple negative cancers have a basallike phenotype Most BRCA1-associated breast cancers are basal like Can we identify a subset of women with triple negative breast cancers likely to harbor a BRCA1 mutation? Does This Have Implications for BRCA1 Testing? Farshid (2006) ER and PR plus morphologic features to predict mutation status Lakhani (2005) ER and basal phenotype to predict mutation status 14

15 Triple Negative Breast Cancers and BRCA1 Mutations Eerola, Br Cancer Research, 2008 Collins, Am J Surg Pathol, 2009 Triple Negative Breast Cancers and BRCA1 Mutations Rakha, Clin Cancer Res, 2009 Basal cytokeratins frequently associated with triple negative breast cancers However, in multivariate analysis basal cytokeratin expression was not predictive of women likely to harbor BRCA1 germline mutations Triple Negative Breast Cancers and BRCA1 Mutations Jury still out on ability to predict mutation status morphologically Studies have used variable starting points and variable definitions of positivity All hampered by small numbers among mutation carriers Current Clinical Status of Expression Signatures for Tumor Classification Not currently used in pathology reports (at least not directly) But, ER, PR, HER2 results could be used to identify luminal, HER2 and basal-like subtypes Given current options for systemic therapy, need to sub-classify beyond ER, PR, HER2 in current practice is debatable 15

16 Immunophenotyping to Approximate Molecular Subtype Using Three Markers Brenton, 2005 ER Luminal A + Luminal B + HER2 - Basallike - Therapeutic Interventions in BRCA1-related Breast Cancers PR HER BRCA1 plays a critical role in repair of DNA double strand breaks Cisplatin is an agent that targets double strand breaks Potential for therapy in BRCA1 associated cancers Silver, JCO, 2010 From Ashworth A, Miami Breast Cancer Conference, 2009 Turner, 2004, Nature Reviews Cancer 16

17 From Ashworth A, Miami Breast Cancer Conference, 2009 Synthetic Lethality in DNA Repair Pathways From Ashworth A, Miami Breast Cancer Conference, 2009 Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer Tutt, Lancet, 2010 Olaparib is well tolerated and highly active in advanced chemotherapy-refractory BRCAdeficient breast cancer Toxicity in BRCA1/BRCA2 carriers was similar to that reported previously in non-carriers First study with olaparib in BRCA-deficient breast cancers provides positive proof of concept for high activity and tolerability of a genetically defined targeted therapy 17

18 Phase II trial of the oral PARP inhibitor iniparib in triple negative advanced breast cancer O Shaughnessy, NEJM, 2011 Iniparib is well tolerated and highly active in advanced chemotherapyrefractory TNC Addition of iniparib to chemotherapy improved outcome without adversely affecting toxicity O Shaughnessy, NEJM, 2011 Question 1 Question 1 The tumor depicted on the next slide is from a 42 year old woman with a BRCA1 germline mutation. The biomarker profile that would most likely be seen in this tumor is: A. ER-, PR-, HER+ B. ER+, PR+, HER2- C. ER-, PR+, HER2- D. ER-, PR-, HER2- E. ER-, PR+, HER2+ 18

19 Question 1 Correct Answer: D. ER-, PR-, HER2- Approximately 80% of cancers that develop in women with germline BRCA1 mutations are have an ER-, PR-, HER2- ( triple negative ) phenotype. In addition, most of these tumors cluster in the basal-like group in gene expression profiling studies and express one or more basal markers by immunohistochemistry. Reference: Atchley DP, et al. J Clin Oncol 2008, 26: Question 2 A 37 year old woman underwent an excisional biopsy for a palpable breast mass. The histologic features of the tumor are illustrated on the next two slides. Which of the following is false regarding tumors of this type? a) Tumors with these features are typically negative for ER, PR and HER2 ( triple negative ) b) Tumors with these features are commonly associated with germline BRCA1 mutations c) Tumors with these features may express EGFR d) Tumors with these features are associated with an excellent prognosis e) Tumors with these features are particularly common in African-American women Question 2 Question 2 19

20 Answer: d. Tumors with these features are associated with an excellent prognosis is false. This is an example of a basal-like breast cancer. These tumors are poorly-differentiated invasive ductal carcinomas that are typically ER/PR/HER2-negative (triple negative), are commonly seen in women with BRCA1 germline mutations, express basal cytokeratins and/or EGFR, are particularly common in African-American women. They are generally associated with a poor prognosis. Question 3 Which of the following is true regarding basal-like breast cancers? a) They are usually low grade invasive ductal carcinomas b) They typically present in older women c) They commonly express basal cytokeratins such as CK5/6 d) They rarely show foci of necrosis e) They typically have an extensive associated component of DCIS Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci 2001;98: Answer: c. They commonly express basal cytokeratins such as CK5/6 Basal-like carcinomas as determined by gene expression profiling exhibit a characteristic constellation of histologic features including tumor circumscription, stromal lymphocytic infiltrate, geographic necrosis and high histologic grade. They are typically ER, PR, and HER2 negative ( triple negative ) and express basal cytokeratins, EGFR as well as other basal markers. These tumors are more common in younger women. Summary Basal-like cancers constitute a heterogeneous group with regard to histologic features, immunophenotype and prognosis No universally accepted definition Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 2006;19:

21 Basal-like Cancers Take Home Message Recently recognized type of invasive breast cancer Grade 3 histology Triple negative Basal CK and/or EGFR expression Poor prognosis Association with BRCA1 mutations 21