triple negative breast cancer 2018 all updates

1. Triple negative BC – YIR 2018!
Dr. Pratik Patil

2.  Abstract 1 : IMPassion130
 Phase III randomized study.
 Locally advanced, unresectable, metastatic, treatment naïve subset of TNBC.
 1:1 randomization was done with 451 patients in both subsets, to receive
atezolizumab + nab-pacli vs nab-pacli + placebo.
 Stratification factors were the presence or absence of liver metastases, use or
nonuse of neoadjuvant or adjuvant taxane treatment, and PD-L1 expression on
tumor-infiltrating immune cells as a percentage of tumor area (<1% [PD-L1
negative] vs. ≥1% [PD-L1 positive]) according to IHC.

3.  Patients received atezolizumab at a dose of 840 mg or placebo, administered
intravenously, on days 1 and 15 and received nab-paclitaxel at a dose of 100 mg
per square meter of body-surface area, administered intravenously, on days 1, 8,
and 15 of every 28-day cycle.

5.  mPFS was 7.2 months with the combination and 5.5 months with chemotherapy alone (hazard
ratio [HR] = 0.80, P = .0025).
 In the PD-L1–positive group, mPFS was 7.5 months with the combination and 5.0 months with
chemotherapy alone (HR = 0.62, P < .0001).
 More than half of patients were alive at the time of analysis, so this was an interim assessment
of overall survival.
 In patients with PD-L1–positive tumors, the median overall survival was 25.0 months with the
combination compared to 15.5 months with standard chemotherapy alone (HR = 0.62).
 In all patients, survival was 21.3 months with the combination vs 17.6 months with
chemotherapy alone, which was not statistically different, likely because of the short follow-up.
 The objective response rate was higher with the combination compared to chemotherapy alone
for all patients (56% vs 46%) and those with PD-L1–positive tumors (59% vs 43%).

7.  Dr. Schmid concluded, “Immune therapy on top of standard chemotherapy
prolonged survival by 10 months in patients with tumors expressing PD-L1.
This combination should become a new treatment option for patients with
metastatic triple-negative breast cancer.”

8.  Abstract 2 : Enzalutamide for the Treatment of Androgen Receptor–
Expressing Triple-Negative Breast Cancer
 Studies suggest that a subset of patients with triple-negative breast cancer (TNBC)
have tumors that express the androgen receptor (AR) and may benefit from an AR
inhibitor.
 This phase II study evaluated the antitumor activity and safety of enzalutamide in
patients with locally advanced or metastatic AR-positive TNBC.
 Primary endpoint : clinical benefit rate at 16 weeks ,32 weeks ,PFS, OS

11.  Treatment - The median duration of enzalutamide treatment was 8.1 weeks
(range, 0.9 to 87 weeks) in the ITT population.
 The most common reason for treatment discontinuation was disease progression.
 Nine patients were still receiving enzalutamide at the time of the data cutoff date
 Efficacy –
 Stage 1. In stage 1, 11 (42.3%) of 26 evaluable patients achieved CBR16;
therefore, the study proceeded to stage 2.

12. Median PFS was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population.
and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup.
Median OS was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT
population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable
subgroup.

13. An updated analysis of OS was performed after an additional 18 months
of follow-up.
Median OS was 12.7 months (95% CI, 8.5 to 16.5 months) in the ITT
population and 16.5 months (95% CI, 12.7 to 20.0 months) in the
evaluable subgroup .

14.  Eight patients discontinued treatment as a result of an AE.
 Events included headache, muscular weakness, anxiety, pleural effusion, back pain,
metastatic pain, general physical deterioration, and CNS metastases.
 The only treatment related grade 3 or greater AE occurring in > 2% of patients was
fatigue (3.4%).
 Serious AEs were reported in 25% of patients and were generally the consequence of
progressive metastatic breast cancer; none were considered related to enzalutamide.
 Twelve patients had grade 5 AEs; 11 of these were deemed consequences of disease
progression.
 One patient, a 62-year-old woman with a history of tobacco use and
hypercholesterolemia, experienced a fatal cardiorespiratory arrest after stent
implantation for a myocardial infarction.

15.  This positive phase II study represents the largest prospective trial of an AR-targeted
treatment of advanced TNBC.
 It met its primary objective, demonstrating enzalutamide’s clinical activity in patients
with AR-positive TNBC.
 In this study, AR expression > 0% was observed in 80% of tumors and AR expression >
10% was observed in 55% of tumors.
 Two other prospective clinical studies of AR inhibitors have been recently published.
TBCRC 011 trial, evaluating bicalutamide, and the French Breast Cancer Intergroup
(UCBG) trial, evaluating abiraterone acetate, enrolled patients whose TNBC had AR
expression of > 10%; these studies reported AR expression > 10% (using AR441) in 12%
and 38% of patients, respectively.

17.  : In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and
anthracycline-based chemotherapy improved pathological complete response
(pCR) rates in patients with triple-negative breast cancer (TNBC).
 Here, they present survival data and the potential prognostic and predictive role of
homologous recombination deficiency (HRD)
 Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin
(MyocetVR ) (PM) or PM plus carboplatin (PMCb)
 The secondary study end points disease-free survival (DFS) and overall survival
(OS) were analyzed. Median follow-up was 47.3 months.
 HRD was among the exploratory analyses in GeparSixto and was successfully
measured in formalin-fixed, paraffin-embedded tumor samples of 193/315
(61.3%) participants with TNBC.
 Homologous recombination (HR) deficiency was defined as HRD score 42 and/or
presence of tumor BRCA mutations (tmBRCA)

18. • A total of 588 patients were
treated within GeparSixto, 273
with HER2-positive tumors and
315 with TNBC confirmed by
central pathology.
• After a median follow-up of
47.3 months, only patients with
TNBC had significantly better
DFS when treated with PMCb
as compared with PM:
• 3-year DFS rate 86.1% (95%
CI 79.4%–90.7%) for PMCb,
75.8% (68.2%–81.9%) for PM
(hazard ratio 0.56, 95% CI
0.34–0.93).

19. • Three-year OS rates were 91.9% (86.2%– 95.4%) for TNBC patients treated with
PMCb compared with 86.0% (79.2%–90.6%) when treated with PM (hazard ratio
0.60, 95% CI 0.32–1.12)

21.  CONCLUSIONS –
 The addition of carboplatin to chemotherapy improved pCR rates for patients with TNBC, but not HER2-positive
disease (DFS benefit by 10% OS by 6%)
 In TNBC cohort, the HRD assay failed to identify a subset of patients most likely to derive benefit from the
addition of carboplatin.
 Trial obtained an HRD result in 193 patients. Of those, 19.8% carried a germline and 28.7% a tumor and germline
BRCA1/2 mutation, supporting additional tmBRCA testing if no gBRCA mutation is detected.
 Of note, the observed difference between germline and somatic mutations is lower than the difference reported for
cancer (gBRCA1/2 mutation 83.0%, tmBRCA1/2 mutation 17.0%)
 Overall, patients with HR deficient TNBC showed about two times higher pCR rates when compared with HR
nondeficient TNBC, which was shown to be independent from the predictive information received by other clinical
variables in multivariate logistic regression models.

23.  Background: GeparOcto compared efficacy and safety of two chemotherapy
regimens in high-risk early breast cancer (BC): sequential treatment with intense
dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly
treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet)
with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC)
 Patients and methods: Patients with cT1c-cT4a-d and centrally assessed human
epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible,
irrespective of nodal status, luminal B-like tumours only if pNþ

25.  Overall, 938 (99.3%) patients underwent surgery, and 227/470 patients who
started iddEPC (48.3% [95%CI 43.7–52.9%]) achieved a pCR (ypT0/is ypN0)
compared with 228/475 who started PM(Cb) (48.0% [95%CI 43.4–52.6%];
continuity corrected χ2-test P = 0.979) corresponding to an OR of 0.99 (95%CI
0.77–1.28).
 pCR (ypT0/is ypN0) rates were not significantly different between treatment
arms.
 Logistic regression analysis, however, showed a significantly higher pCR rate
only in the LPBC subgroup for patients treated with iddEPC compared with
PM(Cb).
 Multivariable logistic regression analysis confirmed that treatment with PM(Cb)
did not predict for achievement of pCR after adjustment for baseline and
stratification factors (OR 0.99; 95%CI, 0.75–1.31; P = 0.931).
 Among the stratification factors, biological subtype (TNBC OR 5.39; 3.20–
9.07, P < 0.001; HER2+ OR 9.78; 5.80–16.5, P < 0.001 compared to HER2-
/HR+) and LPBC (OR 2.28; 1.48–3.52, P < 0.001 compared to no LPBC) were
independent predictors for achievement of pCR.

26.  Conclusion :
 The iddEPC regimen, in particular, yielded impressing results with persistently
higher OS rates compared with conventionally scheduled chemotherapy (absolute
OS benefit of 10% after 10 years irrespective of ER status) and manageable
toxicity.
 The GeparOcto study - randomising the iddEPC regimen against experimental
PM(Cb). PM(Cb) did not result in higher pCR rates compared with iddEPC but
led to more treatment discontinuations and was associated with significantly
higher rates of nonhaematological, especially pulmonal, toxicity.

27.  The dose-dense weekly regimen of PM(Cb) was first investigated in GeparSixto and showed significantly higher pCR
rates and improved DFS in TNBC when weekly carboplatin was added to paclitaxel and nonpegylated liposomal
doxorubicin.
 It was therefore chosen for further evaluation and direct comparison to the well characterised iddEPC regimen.
 In GeparOcto, treatment with PM(Cb) did not predict for higher pCR after adjustment for baseline and stratification
factors.
 Stratification factors – biological subtype, LPBC, TILs
 In GeparOcto, patients with LPBC had a significant, 19% higher pCR rate when treated with iddEPC compared with
PM(Cb) with a significant test for interaction, likely due to the higher dose-intensity of iddEPC as compared with
PM(Cb) with significantly more dose delays, dose reductions and complete treatment discontinuations observed in the
latter group.
 Main reason for differences in treatment modification were non-haematological toxicities causing dose delays in 25.7%
versus 52.8% (P < 0.001) and dose reductions in 27.2% versus 42.3% (P < 0.001) of patients, respectively.
 These numbers are in line with earlier reports from the phase III AGO-ETC and phase II GeparSixto trials [6,15].

28.  Overall, more patients in the PM(Cb) arm discontinued treatment (16.4% versus
34.1%; P < 0.001), mainly due to AEs.
 As expected, haematological AEs were more frequent in the iddEPC arm, but
rates of any non-haematological grade 3 AEs were again higher in the PM(Cb)
arm (43.2% versus 52.0%; P Z 0.008).
 , among the high-grade AEs, pneumonia was reported in four (0.9%) patients in
the iddEPC and 31 (6.5%) in the PM(Cb) arm (P < 0.001) and pneumonitis, which
was a predefined AESI, in 0 (0%) and 12 (2.5%), respectively (P < 0.001).

29.  Despite a pronounced and significantly higher incidence of haematological toxicity,
iddEPC is a more feasible regimen with better treatment adherence due to the lowaer rate
of non-haematological toxicities.
 Overall, 2618 patients have been treated with iddEPC in the AGO-ETC , GAIN-1 and
GeparOcto trial and only three treatment-related deaths have been reported, corresponding
to a mortality rate of 0.1%, which is lower in comparison to conventionally dosed
chemotherapy.
 Long-term toxicity data need to be awaited.
 So high-risk early-stage BC patients, non-inferiority of weekly PM(Cb) in comparison
with iddEPC could not be shown. Interestingly, patients with LPBC achieved a
significantly higher pCR rate with iddEPC than with PM(Cb).
 iddEPC appeared to be more feasible than PM(Cb) in high-risk early BC patients and
should be considered as one of the effective dose-dense regimens either in the adjuvant or
neoadjuvant setting

30.  Delayed Initiation of Adjuvant Chemotherapy Associated With Worse
Outcomes in Patients With Triple-Negative Breast Cancer
 The researchers retrospectively analyzed data - 687 patients with stage I to III
TNBC who had undergone surgery and later received either anthracyclines or
anthracyclines plus taxane-based chemotherapy.
 The patients’ mean age at diagnosis was 49.15.
 The median follow-up was 101 months, and
 the median time to chemotherapy was 41 days.
 The researchers found that 189 patients received chemotherapy at or before 30
days after surgery; 329, between 31 and 60 days; 115, between 61 and 90 days;
and 54 started chemotherapy beyond 90 days after surgery.

31.  The researchers found that as the time to starting adjuvant chemotherapy
increased, the 10-year disease-free survival rate decreased: 81.4%, 68.6%, 70.8%,
and 68.1% among patients who received chemotherapy at ≤ 30, 31–60, 61–90, ≥
91 days, respectively (P = .005).
 The 10-year overall survival rate also decreased as the time to starting adjuvant
chemotherapy increased: 82%, 67.4%, 67.1%, and 65.1% among patients who
received chemotherapy at ≤ 30, 31–60, 61–90, ≥ 91 days, respectively (P = .003).

32.  In their multivariate analysis of how the extent of delay in starting chemotherapy
impacted an increased risk for disease recurrence and death, the researchers found time
to chemotherapy was an independent prognostic factor for recurrence-free survival and
overall survival.
 Patients with a time to chemotherapy of 31–60 days (hazard ratio [HR] = 1.92; 95%
confidence interval [CI] = 1.225–2.998); 61–90 days (HR = 2.38; 95% CI = 1.354–
4.172); and ≥ 91 days (HR = 2.47; 95% CI = 1.250–4.886) had worse survival
compared with those who initiated treatment in the first 30 days after surgery.
 Patients with a time to chemotherapy of 31–60 days (HR = 1.94; 95% CI = 1.243–
3.034), 61–90 days (HR = 2.45; 95% CI = 1.402–4.265), and ≥ 91 days (HR = 2.79;
95% CI = 1.418–5.506) had worse survival compared with those who initiated
treatment in the first 30 days after surgery.