1) BRCA1 and BRCA2 are tumor suppressor genes whose mutations significantly increase the risk of breast and ovarian cancers. Testing for BRCA mutations can help determine appropriate cancer screening and prevention strategies. 2) The HER2 receptor promotes cancer cell growth in around 20-30% of breast cancers. Drugs like trastuzumab, pertuzumab, lapatinib, and T-DM1 target HER2 and have improved outcomes for HER2-positive breast cancer. 3) Newer agents for breast cancer treatment include CDK4/6 inhibitors, PI3K inhibitors, everolimus, neratinib and immunotherapies which are being used alone or in combination with other drugs for

1. ROLE OF BRCA, HER2-NEU AND NEWER
AGENTS IN CARCINOMA BREAST
Dr. Aditya Singla

2. GENETICS OF BREAST CANCER
• Heterogeneous disease
• 20-30% familial breast cancers
• Breast cancer genes-
 High penetrance genes
 Intermediate penetrance genes
 Low penetrance genes

3. BRCA
• Marie Claire King
• BRCA1- 17q21
• BRCA2- 13q12-13
• Tumor suppressor gene
• Double strand DNA repair via homologous recombination.

4. BRCA
• BRCA1- Breast, ovary, prostate, colon.
• BRCA2- Male breast, ovary, prostate,
pancreas, melanomas.
• Autosomal dominant inheritance.
• 10-30 times more risk of breast cancer in BRCA mutated women
resulting in nearly 85% lifetime risk.
• Lifetime risk of 50% for ovarian cancer.

5. PROBABILITY OF BRCA1 MUTATIONS
SCENARIO PROBABILITY
Mother/ Father proven carrier 50%
<40yr breast cancer patient with a first
degree relative with breast cancer
5%
<60yr B/L breast cancer patient with a
first degree relative with breast cancer
5%
<30yr breast cancer patient and a first
degree relative with ovarian cancer
20%

6. NCCN SCREENING GUIDELINES
• Annual clinical and BSE prior to age 25yr
• Annual mammography/ MRI after 25 yr
• Annual pelvic examination with TVS/ color doppler
examinations of ovaries with CA-125, starting from 25-35yrs.

7. BRCAPRO
• It is a statistical model with associated software for assessing
the probability that an individual carries BRCA1/BRCA2
mutation.

8. BRCA1 MUTATION
• More aggressive
• High histology grade
• Young patient
• High proliferation rate
• Aneuploidy
• TNBC

9. SIGNIFICANCE OF BRCA IN TREATMENT DESIGN
• The risk of both contralateral primary breast cancer and
ovarian cancer is substantially higher in patients with
BRCA1/2.
• Oophorectomy decreases the risk I/L breast cancer while
Tamoxifen decreases the C/L breast cancer recurrence.
• BCT f/b chemotherapy has been found to reduce the in breast
relapse rate.

10. TRIALS
• Ten-Year Multi-Institutional Results of Breast-Conserving
Surgery and Radiotherapy in BRCA1/2-Associated Stage I/II
Breast Cancer – Pierce et al
 160 BRCA1/2 patients matched 445 sporadic breast cancer
patients.
 IBTR reduced by prophylactic B/L Oophorectomy
 C/L breast cancer recurrence reduced by Tamoxifen therapy
Pierce et al. journal of clinical oncology 2006;24(16);

11. TRIALS
• CONTRALATERAL BREAST CANCER RISK IN BRCA1/2
MUTATION CARRIERS-Graeser et al
 2020 women with U/L breast cancer with BRCA1/2+
 1996-2008
 Risk of C/L breast cancer increased in BRCA1/2 patients
 Risk more in BRCA1 patients(1.6 times more)
 Young age significantly a/w increase risk of C/L breast cancer
in BRCA1/2 patients.
Graese et al.Journal of clinical oncology. 2009;27(35)

12. TRIALS
• Pierce et al
• 655 patients with BRCA1/2+ randomized into MRM and BCS
arms
• In breast tumor relapse more in BCS arm
• In breast tumor relapse reduced by adding chemotherapy to
BCS arm.

13. PROPHYLACTIC MASTECTOMY AND
OOPHORECTOMY
• 90% reduction after PBM*
• PBSO reduces cancer incidence and mortality
of ovary and fallopian tube carcinomas.
• PBSO also reduces breast cancer incidence
by 50% if done in pre menopause women**
*Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2
mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22:1055–1062.
**Meindl A, Ditsch N, Kast K, et al. Hereditary breast and ovarian cancer: new genes, new treatments, new concepts. Review.
Dtsch Arztebl Int. 2011;108:323–330.

14. HER2 NEU AGENTS

15. HUMAN EPIDERMAL GROWTH FACTOR
RECEPTOR 2

16. HUMAN EPIDERMAL GROWTH FACTOR
RECEPTOR 2
• HER2(ErbB2)- Member of receptor tyrosine kinases.
• HER1/ErbB1, ErbB3 and ErbB4.
• HER2 amplification results in deregulation of G1/S phase of
cell cycle control via Upregulation of cyclins D1,E and cdK6 as
well as P27 degradation.
• So HER2 amplification a/w accelerated cell growth and
proliferation with poor clinical response.

17. TRASTUZUMAB
• Monoclonal antibody used to treat HER2 receptor positive
breast cancer.
• Approved for medical use in 1998 in USA
• HER2 gene amplified in 20-30% of breast cancer patients.
• Induces an immune mediate response resulting in down
regulation and internalization of HER2 receptor.
• S/E – Cardiac dysfunction including CHF.

18. STUDIES
• Improves OS in late stage HER2 positive breast cancer
patients.*
• In early stage HER2-positive breast cancer, it reduces the risk
of cancer returning after surgery. The absolute reduction in
the risk of cancer returning within 3 years was 9.5%, and the
absolute reduction in the risk of death within 3 years was
reduced by 3%. **
*N Engl J Med. 357 (1): 39–51. doi:10.1056/NEJMra043186. PMID 17611206.
**Cochrane Database Syst Rev. 4: CD006243. doi:10.1002/14651858.CD006243.pub2. PMID 22513938.

19. STUDIES IN METASTATIC BREAST CANCER

20. STUDIES IN EARLY STAGE BREAST CANCER

21. DURATION
• One year of treatment is generally accepted, based on current
clinical trial evidence that demonstrated the superiority of
one-year treatment over none.*
*Piccart-Gebhart MJ, MJ; Procter M; Leyland-Jones B; et al. (2005). "Trastuzumab after adjuvant chemotherapy in HER2-
positive breast cancer". New England Journal of Medicine. 353 (16): 1659–1672. doi:10.1056/NEJMoa052306.
PMID 16236737.

22. BIOSIMILAR
• A biosimilar product is a biological product that is approved
based on a showing that it is highly similar to an FDA-
approved biological product, known as a reference product,
and has NO clinically meaningful differences in terms of safety
and effectiveness from the reference product.
• Herceptin- Rosche
• Companies developing biosimilars after rosche patent got
expired in 2014 in Europe and will be expired in 2019 in USA.
• In India first biosimilar was from Mylan and Biocon.

24. PERTUZUMAB
• Monoclonal antibody.
• Discovered by Genetech in 2012.
• It inhibits the dimerization of HER2 with other HER receptors.
• S/E – cardiac dysfunction, loss of hair, diarrhea, neutropenia,
hypersensitivity, URTI.

25. USE
• Pertuzumab is administered as an intravenous infusion in
combination with trastuzumab and docetaxel as a first line
treatment for HER2-positive metastatic breast cancer.*
*"Perjeta Label" (PDF). FDA. March 2016. Retrieved 2 November 2016

26. LAPATINIB
• Oral drug
• Dual TKI, inhibiting HER2 and EGFR pathways.
• Approved in 2007 in USA by GSK under the brand name of
Tykerb and Tyverb.
• S/E- diarrhea, fatigue, nausea, QT prolongation

27. USE
• Lapatinib is used as a treatment for women's breast cancer in
treatment-naive, ER+/EGFR+/HER2+ breast cancer patients.
• Patients who have HER2-positive advanced breast cancer that
has progressed after previous treatment with other
chemotherapeutic agents, such as anthracycline, taxane
derived drugs, or trastuzumab.*
*Geyer CE, Forster J, Lindquist D, et al. (December 2006). "Lapatinib plus capecitabine for HER2-positive advanced
breast cancer". N. Engl. J. Med. 355 (26): 2733–43. doi:10.1056/NEJMoa064320. PMID 17192538.

28. TRASTUZUMAB EMTANSINE(TDM-1)
• Antibody drug conjugate consisting of trastuzumab and
Emtansine (DM1).
• FDA approved in 2013 by Genetech under trade name of
Kadcyla.
• Trastuzumab alone stops growth of cancer cells by binding to
the HER2 neu receptor, whereas DM1 enters cancer cells and
destroys them by binding to tubulin.
• S/E- Fatigue, nausea, thrombocytopenia, hepatotoxic,
cardiotoxic, ILD, neuropathy.

29. USE
• Treatment of HER2-positive Metastatic breast cancer in
patients who have been treated previously with trastuzumab
and a Taxane, and who have already been treated for mBC or
developed tumor recurrence within six months of adjuvant
therapy.*
• EMILIA study-trastuzumab emtansine versus capecitabine plus
lapatinib; TDM1 showing improved PFS,OS. **
*Full Prescribing Information for Kadcyla" (PDF). Genentech. Retrieved 2012-02-23
**Verma, S; Miles, D; Gianni, L; et al. ( ) (November 2012). "Trastuzumab emtansine for HER2-positive advanced breast cancer". N. Engl. J.
Med. 367 (19): 1783–91. doi:10.1056/NEJMoa1209124. PMC 5125250 . PMID 23020162.

30. REGIMENS
• For INVASIVE BREAST CANCER-
 AC f/b T + Trastuzumab
 AC f/b T + Trastuzumab+ Pertuzumab
 Dose dense AC f/b Pacli+ Trastuzumab
 TCH
 TCH+Pertuzumab
 Pacli+Trastuzumab

31. REGIMENS
• Recurrent or metastatic HER2+:
 Pertuzumab+Trastuzumab+Docetaxel
 T-DM1
 Paclitaxel+carboplatin+Trastuzumab
 Trastuzumab+Paclitaxel
 Trastuzumab + Vinorelbine
 Trastuzumab+ Capecitabine
 Lapatinib+ Capecitabine
 Trastuzumab + Capecitabine

32. NEWER AGENTS

33. EVEROLIMUS
• EVEROLIMUS+EXEMESTANE- FDA approved in hormone and
chemotherapy resistant breast cancer patients.
• BOLERO trial*
• Everolimus+exemestane VS exemestane
• Prolong PFS
*Yardley DA, Noguchi S, Pritchard KI, et al. : Everolimus plus exemestane in postmenopausal patients with HR + breast cancer:
BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870–84. 10.1007/s12325-013-0060-1

34. PI3K INHIBITORS
• Buparlisib, pictilisib, alpelisib, and taselisib – role being
investigated.
• Phosphatidylinositol 3-kinase inhibitors
• Enzyme participating in intracellular signalling pathway.

35. CDK4/6 INHIBITORS
• Palbociclib- Paloma clinical trials*
• Ribociclib-MONALESSA study
• Abemaciclib- MONARCH 1 clinical trials**
• In metastatic setting, progressing on 1/2 lines of
chemotherapy.
*Finn RS, Crown JP, Lang I, et al. : The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus
letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-
1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35. 10.1016/S1470-2045(14)71159-3
**Dickler MN, Tolaney SM, Rugo HS, et al. : MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor,
as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. ASCO Annual Meeting.
Abstract 510. Presented June 3, 2016.2016.

36. TKI
• Neratinib- TKI
• Given after trastuzumab
• ExteNET study*
• Improve 2yr DFS.
*Chan A, Delaloge S, Holmes FA, et al. : Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast
cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367–
77. 10.1016/S1470-2045(15)00551-3

37. IMMUNOTHERAPY
• Anti-CTLA4 and anti-PD-1 and PDL-1: FDA approved.

38. ERIBULIN
• Non Taxane
• Tubulin sequestration
• EMBRACE trial*
• For patients failing on >2 lines of chemotherapy lines
including Taxanes and anthracyclines.
• Peripheral neuropathy
*Cortes J, Shaughnessy JO, Blum JL, Vahdat LT, Petrakova K, Chollet P, et al. Eribulin monotherapy versus treatment of physician
choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open label randomized study. Lancet. 2011;377:914–

39. OPLAPARIB
• Inhibiting enzyme poly ADP ribose polymerase
• PARP #
• 400mg BD
• Tutt A, Robson M, Garber JE, Dornchek SM, Audeh MW, Weitzel JN, et al. Oralpoly (ADP ribose) polymerase inhibitor olaparib
in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof of concept trial. Lancet. 2010;376:235–44

40. CABAZITAXEL+ CAPECITABINE
• In Taxane resistant cases
• Cabazitaxel is a novel tubulin binding taxoid
• Villannueva et al.
• Median time to progression was 4.9 months
• Villanueva C, Awada A, Campone M, Machiels JP, Besse T, Magherini E, et al. A multicenterd dose escalating study of
cabazitaxel in combination with capecitabine in patients with metastatic breast cancer progressing after anthracyclines and
taxanes treatment: A phase 1/2 study. Eur J Cancer. 2011;47:1037–45.

41. CAPECITABINE+ IXABEPILONE
• Ixabepilone act as a disruptor of chromosome segregator.
• Sparano et al.*
• overall response rate- 43%
• Time to response-6.6 weeks
• Median progression free survival- 6.24 months
*Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, et al. Randomized phase 3 trial of ixabepilone plus capecitabine
versus capecitabine in patients with metastatic breast cancer previously treated with an anthracyclines and taxanes. J Clin
Oncol. 2010;28:3256–63.

42. MOTESANIB+PACLITAXEL
• Motesanib – VEGFTKI#
• Martin et al*
• overall response rate - 49%
• Median PFS- 9.5 months
*Martin M, Roche H, Pinter T, Crown J, Kennedy MJ, Provencher L, et al. Motesanib, or open – label bevacizumab, in combination
with paclitaxel, as first line treatment for HER2 negative locally recurrent or metastatic breast cancer: A phase 2,
randomized, double-blind, placebo-controlled study. Lancet Oncol. 2011;12:369–76.

43. THANK YOU!!