Triple-Negative Breast Cancer Seeing Positive Results

Linda Brookes, MSc


November 11, 2016

Triple-negative breast cancer (TNBC) is defined negatively, by what it lacks—namely, expression of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor 2 (HER2). It is heterogeneous in terms of intrinsic phenotype, and there is some overlap with the BRCA-related breast cancers, explained Elżbieta Senkus, MD (Medical University of Gdańsk, Poland), co-chair of an educational session devoted to TNBC at the 2016 Congress of the European Society for Medical Oncology.

By classic pathology, a number of tumor types can present as TNBC, the most frequent being high-grade ductal carcinoma. "So it is clear that no single treatment is going to be effective for all these tumor types in all these patients," Dr Senkus stressed. Gene expression analysis of TNBC tumors has identified six subtypes: basal-like (BL1 and BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR), plus an unstable group, the most common subtypes being IM, M, and BL.[1] The subtypes differ by sensitivity to chemotherapy, with a pathologic complete response (pCR) rate to neoadjuvant chemotherapy ranging from 0% to 50%.[2]

TNBC remains a breast cancer subtype with limited options for treatment and a median survival in the range of 20 months.[3] However, a number of therapeutic targets identified for TNBC are currently undergoing intensive research.

Targeting DNA Repair Mechanisms

Multiple "omic" analyses of TNBC have consistently identified a subgroup of TNBC patients with defects in DNA repair, noted Rebecca Dent, MD (Duke-NUS, National University of Singapore and National Cancer Centre, Singapore). These tumors are phenotypically and molecularly similar to BRCA1-associated breast cancers ("BRCAness"). Like in carriers of BRCA1 mutations, the BRCA1 pathway is abnormal in patients with sporadic basal-like breast cancer. All of these patients have tumors with a deficiency in the homologous recombination repair mechanism involved in repairing double-stranded DNA breaks. Other genes, as well as methylation of BRCA1/2, somatic mutation, and other epigenetic mechanisms, have also been implicated in homologous recombination deficiency (HRD).

We forget that some of the older chemotherapies are highly beneficial in TNBC.

Many chemotherapies are DNA interacting, such as cyclophosphamide, which is an alkylating agent; platinum agents, which form adducts with DNA; and anthracyclines, which have DNA intercalating/interstrand cross-linking action, Dr Dent explained. "We forget that some of the older chemotherapies are highly beneficial in TNBC," she said. "Very important data" showed that in patients with node-negative breast cancer treated with the classic cyclophosphamide, methotrexate, and fluorouracil (CMF) regimen, benefit from chemotherapy vs no treatment was greatest in the TNBC subgroup (hazard ratio, 0.46; P = .009),[4] likely due to higher dosing of cyclophosphamide in CMF vs the cyclophosphamide, epirubicin, fluorouracil combination (100 mg/m2 vs 75 mg/m2), Dr Dent said. In BEATRICE, the first large, randomized, phase 3 trial in TNBC patients, Dr Dent noted that "although addition of bevacizumab to chemotherapy did not contribute to improving outcomes, the 3-year OS was over 80% in both groups, well over 10% of what was anticipated.[5] This is because this is a group that benefits more from chemotherapy, especially alkylating agents," she concluded. "So we know now that our threshold to treat TNBC is lower and that these patients in the adjuvant context are doing better."

Mining the Possibilities of Platinums

There is renewed interest in platinum-based chemotherapy in TNBC, Dr Dent noted. This approach was abandoned for many years because of concerns about toxicity and the greater activity with taxanes, she recalled. However, following preclinical evidence supporting the superiority of platinums over taxanes in germline BRCA (gBRCA)-related breast cancer, researchers are again looking at platinums because of their DNA cross-linking mechanism of action. A proof-of-concept study reported a pCR of 61% with cisplatin neoadjuvant therapy in gBRCA1 mutation carriers.[6] In the phase 2 GeparSixto trial, the addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increased the proportion of TNBC patients who achieved a pCR.[7] This result formed the basis for the ongoing INFORM study, which will determine whether pCR rate with neoadjuvant cisplatin is ≥ 20% greater than pCR with doxorubicin/cyclophosphamide in women with stage II/III breast cancer and a gBRCA1/2 mutation.[8]

The TNT trial showed that in gBRCA mutation carriers, platinums should be incorporated very early in the metastatic setting.

The possibility of a role for platinums in TNBC and non-gBRCA1 disease remains the subject of debate. The TNT trial provided no evidence that unselected advanced TNBC patients are more likely to respond to first-line carboplatin than to docetaxel.[9] However, subgroup analysis of patients with gBRCA1/2 had a greater overall response rate (ORR) with carboplatin vs docetaxel (68% vs 33%; P = .03). "The important message from this trial is that we should not give platinums in metastatic non-gBRCA carriers," Dr Dent said. "The TNT trial showed that in gBRCA mutation carriers, platinums should be incorporated very early in the metastatic setting." In PrECOG, a trial of neoadjuvant platinum, gemcitabine, and iniparib, the HRD score was able to identify TNBC tumors, including BRCA1/2 nonmutated tumors that were more likely to respond to platinum-containing therapy.[10]

Is PARP Inhibition Monotherapy in Sight?

A proof-of-concept study for poly (adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with BRCA1/2 mutations and advanced breast cancer that showed an "impressive" 41% ORR with olaparib[11] has been confirmed in other studies of PARP inhibition, and "numerous" randomized clinical trials are ongoing in gBRCA, including EORTC 1307/BIG 5-13 (BRAVO; niraparib),[12] EMBRACA (talazoparib),[13] and OlympiaD (olaparib).[14] "We are not seeing single-agent therapy response, though, and it is difficult to combine potent PARP inhibitors with chemotherapy because of tolerability," Dr Dent noted. The recently reported I-SPY2 trial of veliparib-carboplatin added to standard therapy resulted in higher rates of pCR than standard therapy alone specifically in TNBC.[15] These findings formed the basis for an ongoing phase 3 neoadjuvant trial comparing standard chemotherapy alone vs carboplatin or vs veliparib plus carboplatin as treatment for TNBC.[16]

Among the studies in this field presented in Copenhagen, Dr Dent highlighted one in which 13 patients with tumors >1 cm and gBRCA mutation all had decreases in tumor volume (average, –78%) following 2 months of talazoparib monotherapy.[17] "These are small numbers but encouraging as we move forward in this group of patients. An expansion cohort to estimate pCR to talazoparib alone within 4-6 months is underway," Dr Dent noted. Another "particularly exciting" study was a phase 2 trial of lurbinectedin, a new anticancer drug that that "blocks trans-activated transcription, induces DNA double-strand breaks, and modulates the tumor microenvironment."[18] ORR was 40.7% and progression-free survival 4.1 months in heavily pretreated patients with gBRCA1/2 metastatic breast cancer. "We anxiously await expansion cohorts with this particular agent," Dr Dent added.

Using Androgen Receptor Blockade

Gene expression analyses indicate that the subset of TNBC patients with tumors that overexpress the androgen receptor (AR)—the LAR subtype—accounts for 11% of all TNBC.[1] However, estimates made on the basis of immunohistochemistry put the prevalence higher, between 22% and 35%,[19] including a recent estimate (unpublished) of 24% by a group led by Hervé R. Bonnefoi, MD (Bordeaux University and Institut Bergonié Cancer Center, France). The risk for distant relapse at 5 years in the LAR subtype is 45%,[1] so it is not an indolent TNBC subtype, Prof Bonnefoi explained.

The proof of principle of AR blockade in AR-positive TNBC was demonstrated in three phase 2 clinical trials in which clinical benefit rate (CBR, defined as complete response + partial response) was used as the primary endpoint. In the TBCR C011 trial, CBR at 6 months in patients treated with bicalutamide was 19%.[20] Although there were no objective responses, a contemporary case report described one patient with an AR-positive tumor who achieved a complete response with bicalutamide within 4 months and remained in complete response 12 months later.[21] "It is important to remind clinicians that bicalutamide is not approved for this indication, but it is on the market and not very expensive," Prof Bonnefoi commented. In the MDV30100-11 trial, enzalutamide was associated with CBRs of 35% and 29% at 4 months and 24 weeks, respectively, and six patients had objective responses.[22] In a trial conducted by Prof Bonnefoi's group with abiraterone, the 6-month CBR was 20.0%, with one complete response and one partial response.[23] "The patient in complete response was still in complete response 3 years later," Prof Bonnefoi noted.

"To improve results in this molecular subtype, we need to better identify molecular apocrine (MA) tumors in the clinic, develop predictors for androgen blockade in MA tumors, and gain a better understanding of the biology of MA tumors, particularly what makes the AR functional in the absence of ER," Prof Bonnefoi stated. Several trials of single-agent therapy are ongoing, including ENDEAR, a phase 3, randomized, international trial in patients with advanced TNBC with no or only one prior line of systemic therapy for advanced disease.[24] Patients receive enzalutamide either with paclitaxel or as monotherapy compared with placebo plus paclitaxel. Phase 2 trials are also underway with enobosarm,[25] orteronel,[26] and seviteronel (phase 1b/2)[27] Combination therapy with androgen blockade is also being studied in phase 1/2 trials (bicalutamide plus the cyclin-dependent kinase (CDK)4/CDK6 inhibitor palbociclib[28] and enzalutamide plus the phosphoinositide 3-kinase inhibitor taselisib[29]).

Immunotherapeutic Approaches

"Breast cancer is suitable for immunotherapy, but we have to work out the best strategy," stated Peter Schmid, MD, PhD (Barts Cancer Institute, St Bartholomew's Hospital, Queen Mary University, London, United Kingdom). Increasing evidence supports TNBC as having unique characteristics that may make it more responsive to immunotherapy, he pointed out. TNBC is highly mutagenic and thus produces high numbers of neoantigens. TNBC is also characterized by an increased number of tumor-infiltrating lymphocytes, which can also facilitate an immune response. TNBC is also associated with increased levels of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression, which provides the rationale for investigating therapeutic strategies targeting the PD-1/PD-L1 axis in these tumors.

After four to five treatments, these TNBC patients progress very quickly, so any treatment that can induce responses is very exciting and gives us hope for our patients.

Early data from three clinical trials of pembrolizumab[30] and the anti-PD-L1 antibodies atezolizumab[31] and avelumab[32] in the setting of heavily pretreated metastatic TNBC have shown durable responses. "After four to five treatments, these TNBC patients progress very quickly, so any treatment that can induce responses is very exciting and gives us hope for our patients," Prof Schmid said. He pointed to "very encouraging signals" particularly with ORRs of 18.5% with pembrolizumab[30] and 19% with atezolizumab.[31] Stable disease was seen in about 26% of patients in each trial, "so just under half of patients derived some kind of benefit," he noted. With atezolizumab, three patients with PD-L1-positive TNBC experienced pseudoprogression, continued treatment, and subsequently demonstrated durable responses.[32] "We also have an excellent safety profile therapy, at least in single-agent therapy," he added.

"Because we know that only a relatively small group of patients benefit from single-agent therapy, we should be thinking about combination therapy to widen the target population and increase efficiency," Prof Schmid suggested. "We can combine immunotherapy with conventional chemotherapy. We have learned in recent years that chemotherapy is probably a form of immune therapy itself, and there is strong interaction between the effects of chemotherapy and immune therapy." Combinations of immunotherapy and novel targeted agents such as PARP inhibitors or MEK inhibitors are under investigation in TNBC, and trials are investigating immunotherapy combinations. The first data from a phase 1b trial examining nab-paclitaxel plus atezolizumab as first-, second-, and third-line therapy were presented last year.[33]

"Atezolizumab was selected because of its positive interaction with taxanes and lack of requirement for steroids," Prof Schmid explained. The results of a small trial should not be overrated, he cautioned, but most of the patients seemed to derive a benefit in the first-line setting (ORR, 66.7%; unconfirmed, 89%).[33] "More interesting were the results in the second- and third-line group—ORR 25% and 28.6%, respectively." In the PD-1-negative group, "there was a clear benefit of the combination" (ORR, 57.1%; stable disease rate, 42.9%), although it was not possible to evaluate the contribution of each individual agent. "This is just the beginning of the story," Prof Schmid stressed. "We have a whole plethora of different checkpoints that we are beginning to understand, many targeted by molecules entering the clinic, and we need to find ways of effectively testing these."


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