MANAGEMENT OF EARLY TRIPLE NEGATIVE BREAST CANCER

1. EARLY STAGE TRIPLE NEGATIVE
BREAST CANCER
A TRUE SUBTYPE?
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2. BREAST CANCER - A HETEROGENOUS ENTITY
• ‘Strategies for subtypes. Dealing
with the diversity of breast cancer’.
• Molecular subtypes - treatment
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3. MOLECULAR SUBTYPES
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5. Molecular subtypes and IHC Markers
• WHO accepted molecular
classification (PAM50 gene sig)
• Luminal A
• Luminal B
• Her2 enriched
• Basal like
• Claudin low
• Expensive, not widely available
• Clinicopathological surrogates
adopted by 13th St Gallen
Conference
• Luminal A like
• Luminal B like(Her2-ve)
• Luminal B like(Her2 +ve)
• Nonluminal Her2 +ve
• Triple negative
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6. • Clinicopathological surrogates
adopted by 13th St Gallen
Conference
• Luminal A like
• Luminal B like(Her2-ve)
• Luminal B like(Her2 +ve)
• Nonluminal Her2 +ve
• Triple negative
• Treatment oriented subtypes -
AJCC 8th
• Luminal A like
• Luminal B like(all are Her2-ve)
• Her2 like
• Basal like(TNBC)
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7. TNBC & Basal like breast cancer
• Defined by absence of ER, PR
and HER2 expression by IHC
• Almost 70-75% of triple negative
breast cancers belong to basal-
like breast cancers
• A small subset is low grade,
comprising mostly rare salivary
gland type tumors and variants
of metaplastic carcinomas
• Defined by gene expression
profiling
• Positive – LMW CKs (CK5, CK6,
CK14 or CK17), EGFR, SMA, P-
cadherin, p53 or c-kit antigen
• Neg - ERα, PgR, HER2 or
“luminal” cytokeratins HMWCKs
(CK8/18/19)
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9. CHALLENGES IN TREATMENT OF TNBC
• Aggressive disease
• Younger age group
• Heterogenous disease (group rather than subtype)
• No targeted therapy
• Controversies regarding ideal treatment in - Neoadjuvant, adjuvant
and metastatic setting
• Failure of application of identified molecular signatures in therapeutic
setting
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10. Peculiarities
• Recurrence rate of 25%
• Brain and visceral metastasis (non-skeletal)
• Average time of relapse 1.3 - 3.3 years (5years and above for others)
• 3m mortality after relapse-75%
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11. TNBC in India
• Prevalence in west v/s India (10-13% v/s 11.8-50%)
• According to SEER data - Asian Indian population is 2nd highest
prevalence
• Younger age group(47 v/s 52years)
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12. Triple negative subtypes
Lehmann-2011
• 6 subtypes:
1. basal-like (BL1 and BL2)
2. mesenchymal (M)
3. mesenchymal stem-like (MSL)
4. immunomodulatory (IM)
5. luminal androgen receptor (LAR)
6. unspecified group (UNS)
• Alternative - BL1 and BL2, M and LAR
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14. • BL1
• Mutations in cell cycle and division
• BRCA1&2
• High grade, high ki67
• Sug-preferential response to antimitotic agents like taxanes(63% PCR rates in
studies when treated with taxanes)
• BL2
• Mutations in growth factor signalling pathways
• Angiogenesis pathway
• BRCA1
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15. • IM type
• Mutations in immune signalling, cytokine signalling, antigen processing and
presentation
• Seen in medullary type of breast cancer
• relatively favourable prognosis
• Mesenchymal and mesenchymal stem cell like
• Mutations related to EMT, ECM receptors, angiogenesis
• Highly dedifferentiated, metaplastic breast cancer, which is characterized by
mesenchymal/sarcomatoid or squamous features and is chemoresistant
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16. • LAR type
• Mutations in pathways of steroid synthesis and androgen/estrogen
metabolism
• ER negative
• Apocrine differentiation
• 2016 modification by Lehmann
• Removal of IM and MSL types
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22. • 15th St. Gallen International Breast Cancer Consensus Conference
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25. Why neoadjuvant chemotherapy
• Assessment of invivo response
• PCR in TNBC 33-50% (vs 7% in HR+ve)
• Highest PCR in basal like >50%
• PCR leads to better log term survival
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26. Regimens
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27. What is the evidence in favour?
• 12 international trials, 11 955 patients
• T2 - 7328 patients (61%), T4d - 482 (4%) nodal disease - 5487 (46%)
• Overall PCR-18%, TNBC-33%
• The most favourable outcomes after pathological complete response were
recorded in hormonereceptor-negative tumours who received trastuzumab
with HER2-positive, mab (EFS: 0·15, 0·09–0·27; OS: 0·08, 0·03–0·22), and in
the triple-negative subgroup
• The association between pathological complete response and long-term
outcomes was strongest in patients with triple-negative breast cancer
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29. • 44 patients
• 27 patients – T1& T2, 26 -N1
• 4 cycles of doxorubicin (60 mg/mm2) and cyclophosphamide (600
mg/mm2) followed by 4 cycles of docetaxel (70 mg/mm2)
• PCR -36%
• Predictors of response to NACT-p53, absence of central necrosis in
core needle biopsy
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32. • N=443 with median f/u of 7.9years
• T1&T2-77%, N0&N1-84%, 77% basal like
• Carboplatin increased PCR from 41% to 54%, with bevacizumab (44% to
52%), both - 60%
• Highest grade 3 toxicities with bevacizumab containing arms - febrile
neutropenia, infection without neutropenia, nausea/vomiting, diarrhoea
and dehydration, bleeding complications, thromboembolic events - 12%
discontinuation
• There is no improvement in EFS with the addition of either bevacizumab
(HR, 0.92; 95% CI, 0.66 to 1.29; P = .64) or carboplatin (HR, 0.94; 95% CI,
0.67 to 1.32; P = .72) - not powered to evaluate survival
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34. • T1&T2 - 82%
• N0&N1 - 92%
• TNBC - 53%
• Median f/u 47.3 months
• PCR-37% v/s 43% with carboplatin (p-0.1), (37% v/s 53% in TNBC, p-
0.005)
• TNBC had a significantly better DFS (p = 0.024) and DDFS ( p = 0.013)
when treated with PMCb
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35. Where lies the controversy?
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36. • stages II and III TNBC treated with NAC or AC between 2010 and 2013
• 19,151 patients, 5,621 (29.4%) received NAC, 13,530 (70.6%) received AC.
• Overall 83.5% of had clinical stage II disease, and 16.5% had stage III
disease, in NACT, 68.4% had clinical stage II disease and 31.6% had stage III
disease
• pCR rate following NAC was 47.4%, and was associated with improved 5
year OS compared to non-pCR (86.2% vs. 62.3%; p<0.0001)
• OS was inferior in TNBC patients treated with NAC, than those treated with
AC (73.4% vs. 76.8% p<0.0001)
• Compared to patients who received ACT, those with RD who were put on
NACT had worse OS (HR = 1.18; P < 0.0001)
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37. • Predictors of non-PCR
• Advanced age
• Stage III
• Black race
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38. • 9 studies, 7 retrospective, 2 prospective
• n = 36,480, 10,728 (29.41%) received NACT and 25,752 (70.59%)
received ACT
• pCR rate of 35%(6 studies)
• Median follow-up of 4.12 years, NACT led to worse OS than ACT with
an HR of 1.59; P = 0.0001
• No significant difference in DFS
• pCR following NACT had significant OS benefits (HR = 0.53; P = 0.04)
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39. • k
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40. Is there a way to predict PCR?
• High levels of tumor infiltrating lymphocytes (TILs) - 31% of the low-TIL patients
achieved pCR compared to 50% of the high-TIL patients.
• Grade 3 tumors with platinum-based neoadjuvant therapy than patients with
lower-grade tumors (probability of 63%)
• Basal like type - 41% of PCR
• BA100 -gene profiling test using RNA classifiers on data from the initial biopsy to
predict pCR or RD for breast cancer NAC - correctly predicted 60.8% (45/74) of
pCR and 85.4% (88/103) of RD patients in the TNBC subset
• Strong unmet need for a predictor of response to neoadjuvant chemotherapy for
TNBC
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41. • prediction model using a nomogram integrating blood tests and pre-treatment
ultrasound findings
• N=88, stage II or III operable TNBC receiving NAC
• data before and after the first cycle of NAC collected from patients between
2012 and 2019
• Five parameters correlated with the probability of pCR
• neutrophil-to-lymphocyte ratio
• platelet-to-lymphocyte (PLR) ratio
• percentage change in PLR
• presence of echogenic halo
• tumor height-to-width ratio.
• Predictive value of almost 87% (30.2% PCR)
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43. • February 2007 through July 2012
• 910 patients
• 84 institutions
• DFS - 82.8% vs. 73.9%
• OS - 94.0% vs. 88.9%
• triple-negative disease - DFS -
69.8% vs. 56.1%
• OS - 78.8% vs 70.3%
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45. BRCA MUTATION
• 10-15% of breast cancers
• 70% are TNBC
• Early onset
• Poorly differentiated, high grade, high proliferating indices
• Higher prevalence of HR - ve and TNBC
• Altered sensitivity to chemotherapy
• Increased to platinum and PARP inhibitors
• Decreased to taxanes
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50. • Olympia trial
• phase 3, double-blind, randomized trial
• 420 centers across 23 countries
• germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant,
high-risk HER2-negative, after definitive local treatment and
neoadjuvant or adjuvant chemotherapy.
• At least six cycles of neoadjuvant or adjuvant chemotherapy
containing anthracyclines, taxanes, or both agents.
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51. • TNBC
• Patients treated with NACT should have had residual disease at surgery &
patients treated with ACT should have had at least T - 2cm/ N1
• HR+ & Her2 -
• NACT - Non PCR with CPS-EG score of 3 or higher
• ACT - at least 4 positive nodes
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52. CPS – EG score
• Scoring system estimates relapse
probability on the basis of clinical
and pathological stage (CPS) and
estrogen-receptor status and
histologic grade (EG)
• The system has been validated for
assessing prognosis after
neoadjuvant chemotherapy.
• More refined stratification by
disease specific survival than
either clinical stage or pathologic
stage.
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53. • 1:1 ratio - olaparib (300 mg) or matching placebo tablets taken orally
twice daily for 52 weeks
• 1836 patients, 82% TNBC, 18% HR+
• Distant 3year disease–free survival was significantly longer among
patients assigned to receive olaparib than among those assigned to
receive placebo(87.5% vs 80.5%)(p=0.001)
• Fewer deaths were reported in the olaparib group (59) than in the
placebo group (86), with a hazard ratio of 0.68
• 95% completed treatment - Few grade 3 adverse events(anemia, low
ANC etc)
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55. Mechanism of action
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56. KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo)
vs placebo + chemo as neoadjuvant therapy followed by pembro vs placebo as
adjuvant therapy for triple-negative breast cancer (TNBC).
• T1c N1-2, T2-4 N0-2
• phase III study of pembro+chemo vs placebo+chemo as neoadjuvant
treatment, followed by pembro vs placebo as adjuvant treatment in
pts with TNBC
• 4 cycles of pembro 200 mg Q3W+paclitaxel (80 mg/m2 QW on d 1, 8,
15)+carboplatin (AUC 5 Q3W on d 1 or AUC 1.5 QW on d 1, 8, 15) and
then 4 cycles of pembro+[doxorubicin (60 mg/m2 Q3W on d 1) or
epirubicin (90 mg/m2 Q3W on d1)]+cyclophosphamide (600 mg/m2
Q3W on d 1) as neoadjuvant therapy.
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58. • PCR 60%
• DFS - 84.5% with pembrolizumab vs 76.8% with placebo; HR: 0.63
• Other results yet to mature
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59. Take home message
• PCR has proven itself to be a surrogate marker for long-term survival
• Prognosis after NACT with residue remains poor
• Neoadjuvant treatment with response assessment after each cycle to
identify patients who would achieve PCR and have survival benefit
• Predictors for PCR - yet to be defined
• Many molecular signatures are not yet translated to clinical
significance
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