Keywords
Triple negative breast cancer, Immunotherapy
Triple negative breast cancer, Immunotherapy
Triple-negative breast cancer (TNBC) is a molecularly diverse1 breast cancer subtype currently defined by what it lacks. With hormone receptor immunohistochemistry (IHC) stains of less than 1% for oestrogen and progesterone2 and the absence of HER2 protein overexpression or HER2 gene amplification (or both)3, TNBC accounts for 12 to 17% of all breast cancers, typically affects younger women and typically carries a poor prognosis4. Metastatic progression in this phenotype is typically marked by early relapse and a predominance of hepatic, pulmonary and central nervous system metastasis5.
Despite, or perhaps because of, its aggressive nature and the lack of current targeted treatments, significant clinical and laboratory research is providing nuanced treatment options. Historically, chemotherapy has been the only viable systemic treatment option for early and advanced disease. However, recently published clinical trials have shown that immunotherapy has an important role in the treatment paradigm of this devastating condition.
Although it is generally accepted that early-stage TNBC is chemotherapy-sensitive, the optimal treatment regimen remains undefined. Neoadjuvant chemotherapy is a standard of care for a locally advanced or inoperable TNBC. A major advantage of this approach is the ability to pre-emptively predict survival according to the presence or absence of a pathological complete response (pCR) at the time of surgery and tailor adjuvant therapy. Patients with TNBC, as opposed to those with the luminal subtypes, are more likely to achieve a pCR with neoadjuvant chemotherapy6. Achieving pCR (defined as no invasive or in situ disease in the breast or lymph nodes) at the time of surgery is associated with a significant improvement in disease-free survival (DFS)7–9; as such, pCR is considered a surrogate outcome end point. However, it is unclear whether changes in pCR will ultimately equate to improvements in overall survival (OS) and thus the use of pCR as a robust trial end point is debated.
Clinicians often adopt an intensive approach with sequential anthracycline and taxane regimens and the evidence for this derives from retrospective, subgroup analyses of clinical trials reported before 2010 (Table 1).
Number of patients with triple-negative breast cancer | Trial arms (number of patients) | Pathological complete response rate | Reference |
---|---|---|---|
96 | Intensified FAC (56) FEC (40) | Intensified FAC: 47% FEC: 13% Combined: 29% | 10 |
120 | FAC or FEC | 17% | 11 |
22 | T-FAC | 45% | 19 |
23 | Anthracycline and taxane | 39% | 12 |
34 | AC ± taxane | 27% | 13 |
47 | D and A | 17% | 14 |
255 | A: FAC or FEC or AC (70) B: T-FAC or T-FEC (125) C: Taxane only (17) D: Other (43) | A: 20% B: 28% C: 12% D: 14% | 6 |
45 | AC → T | 34% | 15 |
21 | Anthracycline and taxane | 38% | 16 |
38 | AC or AT Or T/cape | 34% | 17 |
22 | Cis | 23% | 20 |
12 | Cp and T | 67% | 21 |
30 | E/Cis/F → T | 40% | 22 |
125 | Platinum and D ± AC | 34% | 23 |
10 | Cis | 90% | 24 |
A, doxorubicin; AC, doxorubicin and cyclophosphamide; Cape, capecitabine; Cis, cisplatin; Cp, carboplatin; D, docetaxel; E/Cis/F, epirubicin and cisplatin and 5-fluorouracil; FAC, 5-fluorouracil and doxorubicin and cyclophosphamide; FEC, 5-fluorouracil and epirubicin and cyclophosphamide; T, paclitaxel.
Anthracyclines alone had reported pCR rates of 14 to 47%10,11, whereas sequential anthracycline and taxane regimens had reported pCR rates of 17 to 39%6,12–17. GeparTrio reported pCR rates up to 57% for TNBC managed with neoadjuvant anthracyclines, cyclophosphamide and taxanes18. Since then, clinical trials have attempted to define which combination of systemic agents results in the highest rates of pCR (Table 2).
Study Phase ClinicalTrials.gov Identifier | Number of patients | Trial arms | Pathological complete response |
---|---|---|---|
PARP inhibitors | |||
BrighTNess25 Phase 3 NCT02032277 | A: 316 B: 160 C: 158 | A: Veliparib + Cp + T → AC B: Placebo and Cp and T → AC C: Placebo and T → AC. | A: 53% B: 58% C: 31% |
Talazoparib26 Phase 2 NCT02282345 | 17 | 24 weeks Tala (no neoadjuvant chemotherapy) | 47%a |
Anthracycline, taxane and platinum combinations | |||
GeparSepto GBG 6927 Phase 3 NCT01583426 | 276 | Nab-pac → EC Pac → EC | Nab-pac: 56% Pac: 37% |
ETNA28 Phase 3 NCT01822314 | 219 | Nab-pac → AC or EC or FEC Pac → AC or EC or FEC | Nab-pac: 41% Pac: 37% |
WSG-ADAPT-TN29 Phase 2 NCT01815242 | 336 | Nab-pac and gem Nab-pac and Cp | Nab-pac and gem: 28.7% Nab-pac and Cp: 45.9% |
Phase 230 NCT01276769 | 91 | T and Cp → surgery → anthracycline EP → surgery → taxane | T and Cp: 38.6% EP: 4% |
GEICAM/2006-0331 NCT00432172 | 94 | EC-D or EC-D and Cp | EC-D: 30% EC-D & Cp: 30% |
Cisplatin-132 NCT00148694 | 28 | Neoadjuvant cis → surgery → adjuvant chemotherapy | 22% |
Phase 133 NCT01090128 | 10 (TNBC cohort) | Nab-pac AC | 100% |
Chemotherapy backbone with or without novel agents | |||
PrECOG 010534 Phase 2 NCT00813956 | 80 | Gemcitabine, Cp, iniparib | 36% |
Cisplatin-2 NCT00580333 | 51 | Cis and Bev | 16% |
CALGB 4060335 Phase 2 NCT00861705 | 454 | T ± Cp ± bev → ddAC | No Cp: 41% with Cp: 54% No bev: 52% Bev: 44% Cp and bev: 60% |
Phase 236 NCT00930930 | 145 | Cis + T ± everolimus | Everolimus: 36% Placebo: 49% |
Phase 237 NCT00600249 | 35 | Cetuximab and D | pCR: 24% |
GeparQuinto GBG 4438 Phase 3 NCT00567554 | 663 | EC → D ± bev | With bev: 39.3% No bev: 27.9% |
Phase 239 NCT00933517 | 47 | Panitumumab and FEC-D | 46.8% |
GeparSixto GBG 6640 Phase 3 NCT01426880 | 315 (TNBC cohort) | T and Liposomal doxorubicin and Bev ± Cp | 53.2% with Cp 36.9% no Cp |
AC, doxorubicin and cyclophosphamide; Bev, bevacizumab; Cis, cisplatin; Cp, carboplatin; D, docetaxel; ddAC, dose dense doxorubicin and cyclophosphamide; EC, epirubicin and cyclophosphamide; EP, epirubicin and paclitaxel; FEC, 5-fluorouracil and epirubicin and cyclophosphamide; gem, gemcitabine; Nab-pac, nab-paclitaxel; pac, paclitaxel; PARP, poly (ADP-ribose) polymerase; T, paclitaxel; Tala, talazoparib; TNBC, triple-negative breast cancer. aReported as residual cancer burden (RCB) and results represent RCB 0, equivalent to pathological complete response (pCR).
Alkylating agents like carboplatin and cisplatin have provided additional improvements in rates of pCR. Given that a proportion of TNBC tumours have a functional alteration in breast cancer gene 1 (BRCA1), analysis of the role of inter-strand cross-linking agents is especially prudent. The coupling of platinum-induced DNA damage and deficiencies in BRCA-associated DNA repair13 has been exploited in phase 2 trials of platinum monotherapy and yielded promising pCR rates of 23 to 90%20,24,32, and rates of pCR were higher amongst BRCA mutation carriers24,32. Although the randomised phase 2 GEICAM 2006-0331 did not lead to a significant improvement in pCR, GeparSixto40 and CALGB 4060335 reported higher rates of pCR with the addition of carboplatin. It is important to note that the addition of carboplatin in these trials led to a significant increase in toxicity and that, for CALGB 40603, the improved pCR rate translated into a modest 5% improvement in 3-year event-free survival, which was not statistically significant35.
In further attempts to manipulate homologous recombination deficiencies inherent to BRCA1 and BRCA2 germline mutant tumours, poly (ADP-ribose) polymerase (PARP) inhibitors have been added to the neoadjuvant cocktail. PARP inhibitors act by inducing synthetic lethality in BRCA-deficient cells whilst sparing cells with preserved BRCA function. The phase 3 BrighTNess clinical trial saw a pCR improvement that was attributable to carboplatin rather than the PARP inhibitor under investigation, veliparib25. PrECOG 0105, a single-arm phase 2 clinical trial of gemcitabine, carboplatin and iniparib, yielded a promising pCR of 36%, and response rates were higher in those tumours with elevated mean homologous recombination deficiency-loss of heterozygosity (HRD-LOH) scores, a DNA-based measure of genomic instability34,41. Although iniparib is no longer considered a true PARP inhibitor42–44, these results are compelling. It is possible that the different PARP agents will have differing efficacy because of PARP trapping45. Certainly, promising pCR rates were seen in patients with germline BRCA-mutated early-stage breast cancers with just talozparib alone26.
Novel agents like the monoclonal antibodies bevacizumab, panitumumab and cetuximab have been assessed with mixed results (Table 2). The randomised phase 3 GeparQuinto reported that an improvement was seen in rates of pCR with the addition of bevacizumab, but the survival analysis did not show a significant difference38.
Although attaining pCR is the goal of neoadjuvant therapy, optimal management of those who do not meet this end point is critical as these patients have a relapse risk that is six to nine times higher than that of patients achieving pCR6,7.
The CREATE-X clinical trial showed that six to eight cycles of adjuvant capecitabine (1250 mg/m2 from days 1 to 14, every 21 days) improved DFS and OS in the TNBC cohort. DFS rates were 69.8% in the capecitabine arm and 56.1% in the control arm (hazard ratio [HR] 0.58 for recurrence, second cancer, or death; 95% confidence interval [CI] 0.39–0.87), and OS rates were 78.8% and 70.3% (HR 0.52 for death, 95% CI 0.3–0.9)46. The importance of targeting adjuvant capecitabine to those with residual disease was recently highlighted by the results of the phase 3 GEICAM/CIBOMA trial. This randomised phase 3 trial of 876 patients who had early-stage TNBC and who had completed standard adjuvant or neoadjuvant polychemotherapy was designed to analyse the impact of adjuvant capecitabine (1000 mg/m2 from days 1 to 14, every 21 days) for all patients with TNBC regardless of their pCR status. There was no significant difference in 5-year DFS and OS between the treatment groups, highlighting the need to choose a treatment-resistant group47. The results of the CREATE-X trial now compel most clinicians to treat early-stage TNBC with neoadjuvant chemotherapy in order to understand who should have capecitabine. Whilst capecitabine should be considered, ongoing trials are evaluating new agents for TNBC with residual disease after neoadjuvant chemotherapy.
The programmed cell death 1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab are monoclonal antibodies designed to release inhibition of the PD-1/PD-L1–mediated immune response, whereas ipilimumab releases inhibition of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-mediated immune response. TNBC tumour cells use the PD-1/PD-L1 and CTLA4 immune pathways to avoid immune surveillance and proliferate but these monoclonal antibodies facilitate an effective immune-mediated and anti-tumour response48.
Pembrolizumab combined with anthracycline and taxane chemotherapy has pushed the pCR boundary even further. Impressive pCR rates of up to 90% have been reported in phase 1b and 2 clinical trials (Table 3).
Study | Number of patients | Trial arms | pCR rate |
---|---|---|---|
I-SPY 252 Phase 2 | 69 | T → AC T and pembro → AC | Control: 22.3% Pembro: 62.4% |
KEYNOTE-17353,54 Phase 1b | 20 | A: pembro → pembro and nab-pac → pembro and AC. B: pembro → pembro and nab-pac 100 mg/m2 and Cp (AUC 6) → pembro and AC C: pembro → pembro and nab-pac 125 mg/m2 and Cp (AUC 5)→ pembro and AC D: pembro → pembro and nab-pac 125 mg/m2 and Cp (AUC 2)→ pembro and AC E: pembro → pembro and T and Cp (AUC 5)→ pembro and AC F: pembro → pembro and T and Cp (AUC 2)→ pembro and AC | A: 60% B: 90% Overall pCR rate (A–E): 60% |
Patient selection for the optimal use of these agents is important and will likely be critical to their success in terms of DFS and OS outcomes, as seen in the CREATE-X and GEICAM-CIBOMA trials. The BCT 1702-CHARIOT clinical trial (ANZCTR N12617000651381) was designed to help guide clinicians in the management of patients with TNBC that is not responding to standard neoadjuvant therapy. The phase 2 clinical trial combines paclitaxel with ipilimumab and nivolumab in eligible patients with a residual TNBC of at least 15 mm and less than 50% reduction in longest diameter of the tumour after completion of four standard cycles of anthracycline chemotherapy. The trial is designed to select out the most at-risk TNBC population to see whether they can derive benefit from the novel combination of therapies as these patients have been reported to have pCR rates of less than 10% and hence the highest risk of dying from their disease49,50. Furthermore, selection and duration of these myriad adjuvant therapies will be important to delineate as the outcomes of ongoing clinical trials (Table 4) are eagerly awaited.
AC, doxorubicin and cyclophosphamide; ddAC, dose dense doxorubicin and cyclophosphamide; ddEC, dose dense epirubicin and cyclophosphamide; DFS, disease-free survival; dRFS, disease recurrence-free survival; EC, epirubicin and cyclophosphamide; EFS, event-free survival; FEC, 5-fluorouracil and epirubicin and cyclophosphamide; iDFS, invasive disease-free survival; OS, overall survival; pCR, pathological complete response; RFI, recurrence-free interval.
Patients with metastatic TNBC experience poorer outcomes when compared with patients with other breast cancer subtypes51. First-line systemic treatment typically includes a taxane or anthracycline combination55, and median OS tends to be 18 months or less56–58. Novel treatment approaches are critical to improve these dire survival outcomes.
The OlympiAD clinical trial randomly assigned patients with advanced HER2-negative breast cancer and a germline BRCA mutation to a PARP inhibitor, olaparib (300 mg twice daily), or standard physician’s choice chemotherapy59. The significant progression-free survival (PFS) benefit favoured olaparib with a median PFS of 7.2 months (versus 4.2 months)59. Subgroup analysis of PFS for randomised stratification factors revealed an outstanding HR for progression of 0.39 (95% CI 0.27–0.57) amongst the TNBC subset, which made up nearly 50% of the treatment cohorts in both arms59.
The EMBRACA clinical trial compared the PARP inhibitor talazoparib (1 mg daily) with protocol-specified standard therapy (capecitabine, eribulin, gemcitabine or vinorelbine) and found a favourable median PFS of 8.6 versus 5.6 months in the standard therapy group (HR for progression or death 0.54, 95% CI 0.41–0.71) with a trend towards an OS benefit, but the data are immature60. Although rates of adverse events were similar in the two treatment arms, patients randomly assigned to talazoparib reported superior quality-of-life outcomes (as recorded by the EORTC QLQ-C30) with a significant delay in the onset of a clinically meaningful deterioration in global health status60.
The results of the randomised phase 3 trials BRAVO (ClinicalTrials.gov Identifier: NCT01905592) using niraparib 300 mg daily61 versus chemotherapy and BROCADE (ClinicalTrials.gov Identifier: NCT02163694) using veliparib or placebo combined with chemotherapy in a similar cohort (germline BRCA mutation-positive) are still pending.
The addition of iniparib to gemcitabine and carboplatin has shown promising results for all patients with metastatic TNBC regardless of their BRCA mutation status. A randomised phase 2 clinical trial showed that the addition of iniparib prolonged the median PFS from 3.6 to 5.9 months (HR for progression, 0.59; P = 0.01) and the median OS from 7.7 to 12.3 months (HR for death, 0.57; P = 0.01)62. The phase 3 clinical trial did not meet the pre-specified co-primary end points, PFS and OS, but did report an efficacy signal for patients randomly assigned to second- or third-line PARP inhibitor therapy62. This is likely because iniparib is no longer considered a true PARP inhibitor for the purposes of clinical research. Although iniparib inhibited PARP-1 function in vitro and was tested in clinical trials for this reason, subsequent studies have shown that the cell killing mechanism of iniparib does not reflect PARP inhibition42–44.
Notably, the Triple-Negative Breast Cancer Trial (TNT) has provided important insights into the role of platinum- and taxane-based chemotherapy63. The trial enrolled 376 patients with either a known deleterious BRCA1/2 germline mutation (and any metastatic breast cancer phenotype) or metastatic TNBC. Although no significant difference was seen in the overall TNT population, a significantly better objective response rate of 68% to carboplatin versus 33% to docetaxel was found amongst the 43 patients with a germline BRCA1/2 mutation63. Furthermore, within this population, a PFS benefit favouring carboplatin (median PFS of 6.8 versus 4.4 months) was found without a corresponding OS benefit63. Once again, the benefit was not reflected in the overall TNT population, where there was no significant PFS or OS advantage to either agent63.
Prior to October 2018, phase 1 and 2 clinical trials evaluating PD-1 protein blockade as monotherapy in advanced TNBC showed disappointing response rates of 5 to 10% in unselected cohorts64–66. These poor response rates likely reflect that breast cancer is not a highly immunogenic solid organ malignancy67. This has been thought to underlie the modest response rates seen with checkpoint inhibitor monotherapy to date; as a result, patients with advanced breast cancer need to be selected for the presence of pre-existing activity of the host immune system68,69. The complexity of this response, when analysed in more detail, is apparent; however, tumour-infiltrating lymphocytes (TILs) simply measured by using light microscopy on hematoxylin-and-eosin–stained slides particularly have provided important insights into this variable response rate70. TILs are mononuclear immune cells that infiltrate tumour tissue and are composed mainly of CD4+ and CD8+ (cytotoxic) T cells71. TILs are an independent prognostic biomarker in breast cancer, and in early-stage, node-positive TNBC, high TILs correlatewith improved survival72,73. In addition to TILs, PD-1 and PD-L1 can be expressed by tumour cells and their presence can be evaluated as part of a detailed pathological examination of the tumour by using proprietary IHC assays74,75. In metastatic TNBC, better response rates were noted with pembrolizumab monotherapy in tumours with higher quantitative levels of TILs76. Ultimately, it is highly likely that all of these immune markers read out a similar signal for selecting patients most likely to respond to PD-1 or PD-L1 inhibition or both.
The recent approval of atezolizumab in advanced TNBC was based on the IMpassion 130 study. IMpassion 130 was a phase 3 registration study that randomly assigned over 900 patients with incurable TNBC who had relapsed 12 months or more after adjuvant chemotherapy to receive either nab-paclitaxel and atezolizumab (a PD-L1 inhibitor) or nab-paclitaxel and placebo. A statistically superior PFS benefit was seen: median PFS values of 7.2 months (95% CI 5.6–7.2 months) in the atezolizumab and taxane arm and 5.5 months (95% CI 5.3–5.6 months) with chemotherapy alone (HR = 0.8, 95% CI 0.69–0.92; P = 0.0025) were reported; among the PD-L1–positive tumours, median PFS values of 7.5 months (95% CI 6.7–9.2 months) and 5 months (95% CI 3.8–5.6 months) were reported (HR = 0.62, 95% CI 0.49–0.78; P <0.0001); hence, the primary end point of the study was met77. Interim OS analysis (60% of events) already showed a trend towards the atezolizumab and taxane combination with median OS values of 21.3 and 17.6 months (stratified HR 0.84, 95% CI 0.69–1.02)77. Furthermore, 40% of the population did not receive any prior chemotherapy. It is likely that this group of patients with metastatic TNBC does much better both in general and with immunotherapy. Still, the first steps have been taken in the field, and we have much work to do to positively impact survival in this population.
Recently, the treatment of both early and advanced TNBC has seen significant improvements in response rates and survival outcomes. The time has now come to stratify and personalise patient management according to response for early-stage disease and to the presence or absence of an immune infiltrate for advanced disease.
Patients with early-stage disease who do not achieve pCR after neoadjuvant chemotherapy should be offered six to eight cycles of adjuvant capecitabine monotherapy, in accordance with the CREATE-X trial. For patients with advanced disease who are PD-L1+, CD8+, or TIL+, optimal treatment would include up-front atezolizumab and nab-paclitaxel. Exposure to a PD-1 or PD-L1 agent (or both) is likely still important for survival in patients who do not receive the combination in the first-line setting. Whether those who have a positive immune infiltrate and a disease-free interval of less than 12 months benefit from this regimen is unknown. Those without a positive immune infiltrate should be referred for a clinical trial that uses combinations of novel agents, chemotherapy and immunotherapy. The TNBC treatment landscape is an ever-evolving space, which epitomises the crucial relationship between laboratory and clinical research. The complex interplay has enabled practise-changing advances in treatment outcomes not seen in TNBC for decades.
BRCA, breast cancer gene; DFS, disease-free survival; OS, overall survival; PARP, poly (ADP-ribose) polymerase; pCR, pathological complete response; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; TIL, tumour-infiltrating lymphocyte; TNBC, triple-negative breast cancer
SL and AB are supported by the National Breast Cancer Foundation of Australia and the Breast Cancer Research Foundation (New York, NY, USA).
Views | Downloads | |
---|---|---|
F1000Research | - | - |
PubMed Central
Data from PMC are received and updated monthly.
|
- | - |
Competing Interests: Heather McArthur has previously consulted or had an advisory role for Merck, Spectrum Pharmaceuticals, Lilly, Amgen, Immunomedics, Pfizer, Genentech, Bristol-Meyers Squibb and Genomic Health. Additionally, Heather was on the expert panel for Lilly in 2017.
Competing Interests: No competing interests were disclosed.
Alongside their report, reviewers assign a status to the article:
Invited Reviewers | ||
---|---|---|
1 | 2 | |
Version 1 02 Aug 19 |
read | read |
Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:
Sign up for content alerts and receive a weekly or monthly email with all newly published articles
Already registered? Sign in
The email address should be the one you originally registered with F1000.
You registered with F1000 via Google, so we cannot reset your password.
To sign in, please click here.
If you still need help with your Google account password, please click here.
You registered with F1000 via Facebook, so we cannot reset your password.
To sign in, please click here.
If you still need help with your Facebook account password, please click here.
If your email address is registered with us, we will email you instructions to reset your password.
If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance.
Comments on this article Comments (0)