Evolving treatment strategies of brain metastases from breast cancer: current status and future direction

Era of new HER2-targeted therapy

Trastuzumab, the first anti-HER2 antibody, is effective at controlling extracranial disease in HER2-positive patients, and has dramatically improved survival. ⁵³ However, due to its large molecular weight (~148 kDa), its delivery across the BBB is limited. ⁵⁴ For this reason, new HER2-directed therapies are currently being developed.

Pertuzumab, a recombinant humanized monoclonal antibody (~148 kDa), binds to a different HER2 site than trastuzumab, preventing HER2/HER3 dimerization and providing complementary action when combined with trastuzumab. ⁵⁵ The CLEOPATRA trial randomized metastatic HER2-positive patients with no prior chemotherapy or HER2-directed therapy into pertuzumab (or placebo)+trastuzumab+docetaxel groups. ⁵⁶ Long-term follow up (median 50 months) revealed that the pertuzumab combination significantly improved OS with an absolute difference of 15.7 months [median (95% confidence interval (CI)), 56.5 months (49.3–not reached) versus 40.8 (35.8–48.3)]. Thus, pertuzumab in combination with trastuzumab and docetaxel became standard first-line therapy in this population. Despite the exclusion of patients with CNS metastases and almost similar incidence of CNS metastases in this trial, the onset of CNS metastases was delayed in the pertuzumab combination group compared with the placebo group [median 15.0 versus 11.9 months, hazard ratio (HR) 0.58, 95% CI 0.39–0.85, p = 0.005]. ⁵⁷ This result shows the potential role of pertuzumab in the treatment of BM. PATRICIA [ClinicalTrials.gov identifier: NCT02536339] is a phase II study assessing the safety and efficacy of pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) with high-dose trastuzumab (6 mg/kg weekly) for HER2-positive patients with progressing CNS metastases after cranial RT (Table 3). In the planned interim analysis of 15 patients, the CNS objective response rate (ORR) per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria was 20%; no new safety signals were observed. ⁵⁸

HER2-targeted tyrosine kinase inhibitors (TKIs) that penetrate the BBB are used in clinical practice and are being investigated in clinical trials, including: lapatinib,^36,59–63 neratinib,^64–67 afatinib,^37,68 tucatinib,^69–73 pyrotinib,^74,75 and epertinib. ⁷⁶ Lapatinib is an orally bioavailable and small dual TKI that binds HER2 and the epidermal growth factor receptor. ⁵⁹ A phase II study of lapatinib as a single agent in pretreated patients was disappointing, with a volumetric CNS ORR of 6%. ⁶⁰ However, when combined with capecitabine in a randomized phase II study, the response rate increased to 38% (Table 1). ³⁶ LANDSCAPE, a phase II study, evaluated lapatinib+capecitabine for HER2-positive patients with previously untreated BM. ⁶¹ Surprisingly, CNS ORR (volumetric) was 65.9% (95% CI 50.1–79.5), suggesting that instead of cranial RT, up-front lapatinib+capecitabine is a feasible first-line treatment for BM in HER2-positive BC. However, this high CNS ORR should be interpreted considering that patients did not receive current, standard, first-line treatment for BM, and needs to be demonstrated in randomized control trials. Recently, a phase I study of 11 patients with CNS metastases illustrated that intermittent high-dose lapatinib (1500 mg bid) is tolerable when alternated with capecitabine. ⁶² The LAPTEM phase I trial assessed lapatinib+temozolomide and showed favorable safety and efficacy. ⁶³ These novel strategies warrant further investigation.

Neratinib is an oral, irreversible TKI of the pan-HER family. ⁶⁴ The Translational Breast Cancer Research Consortium (TBCRC) 022 initiated a phase II trial to investigate the efficacy of neratinib for patients with pretreated, progressive BM in HER2-positive BC. This trial consists of three cohorts: Cohort 1, neratinib monotherapy; Cohort 2, neratinib with surgical resection; and Cohort 3, neratinib+capecitabine without (3a) and with (3b) previous lapatinib treatment. In Cohort 1, 40 patients were enrolled, and 78% of patients had a history of receiving WBRT. ⁶⁵ Only three patients showed a partial response in CNS lesions according to composite criteria (ORR 8%). The composite CNS ORR in Cohort 3a and 3b were 49% (95% CI 32–66) and 33% (95% CI 10–65), respectively. ⁶⁶ Median progression-free survival (PFS) and OS were 5.5 and 13.3 months in Cohort 3a, respectively, and were 3.1 and 15.1 months in Cohort 3b, respectively. The most common grade ⩾3 toxicity was diarrhea in Cohort 1 (25%) and Cohort 3a/b (29%).^65,66 TBCRC 022 also designed a Cohort 4 [ClinicalTrials.gov identifier: NCT01494662] to evaluate neratinib and ado-trastuzumab emtansine (T-DM1; Table 3). The results of NALA, a randomized phase III trial, were presented in 2019. ⁶⁷ Neratinib+capecitabine was compared with lapatinib+capecitabine in metastatic HER2-positive patients, as a third- or later-line HER2-directed therapy. PFS improved (HR 0.76; p = 0.006), and OS tended to be longer (HR 0.88; p = 0.209) in the neratinib combination group. This trial excluded active BM, but asymptomatic CNS metastases were included. Neratinib+capecitabine postponed time to intervention for symptomatic CNS (overall cumulative incidence, 22.8% versus 29.2%; p = 0.043). However, grade 3 diarrhea in these patients was more frequent than in lapatinib+capecitabine-treated patients (24.4% versus 12.5%).

Afatinib is an oral, irreversible HER1 and HER2 TKI. ⁶⁸ A total of 121 patients with progressive/recurrent BM while receiving HER2-targeted therapies (trastuzumab, lapatinib, or both) were randomized into afatinib alone, afatinib+vinorelbine, or treatment of physician’s choice (TPC) in a phase II study (Table 1). ³⁷ The primary endpoint was clinical benefit 12 weeks after randomization and was assessed as follows: (a) no progression of CNS per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1; (b) no worsening of tumor-related neurological signs or symptoms; (c) no corticosteroid dose increase; and (d) absence of extra-CNS disease progression. Unexpectedly, clinical benefit was mostly achieved in the TPC group (41.9%), though was not statistically significant. In addition, toxicity profiles were worse in afatinib-containing treatments. These disappointing results have almost put an end to further afatinib research. A randomized phase II trial [ClinicalTrials.gov identifier: NCT04158947] is preparing, which will investigate the combination of another HER2-targeted agent, T-DM1, with afatinib (Table 3).

Another promising agent is tucatinib, an orally administered, selective, and reversible HER2 TKI, which reduces diarrhea and rash compared with other HER2 TKIs. ⁶⁹ Tucatinib with capecitabine and trastuzumab was tested in a phase I study for metastatic HER2-positive patients with or without treated stable BM. ⁷⁰ Twelve patients treated with 300 mg twice-daily tucatinib had measurable BM and five patients (42%) experienced brain-specific objective response by modified RECIST. A phase II randomized, double-blind study, HER2CLIMB, validated the treatment outcomes of this regimen and further included patients with BM which did not need immediate local intervention. ⁷¹ The tucatinib combination prolonged PFS (HR 0.54, 95% CI 0.42–0.71; p <0.001) and OS (HR 0.66, 95% CI 0.50–0.88; p = 0.005) compared with placebo. For patients with BM, the addition of tucatinib still improved PFS (HR 0.48, 95% CI 0.34–0.69; p < 0.001). As other combination regimens, phase I studies of tucatinib combined with trastuzumab [ClinicalTrials.gov identifier: NCT01921335; Table 3] or T-DM1, even enrolling patients with progressive CNS lesions unless requiring immediate local therapy, reported CNS ORR as 8% and 36%, respectively.^72,73 Now, a randomized, double-blinded, phase III study [ClinicalTrials.gov identifier: NCT03975647], also known as HER2CLIMB-02, is recruiting patients with advanced or metastatic HER2-positive BC. The criteria for enrollment of patients with BM are the same as in the previous phase I study. Patients will be randomly assigned to T-DM1+tucatinib or placebo, and the primary endpoint is PFS. Tucatinib has received US Food and Drug Administration approval in combination with trastuzumab and capecitabine for women with previously treated advanced HER2+ breast cancer, with or without BM.

Pyrotinib is an oral, irreversible TKI targeting HER1, HER2, and HER4. ⁷⁴ In a randomized phase III study, pyrotinib was assessed against placebo, both administered with capecitabine, for patients with metastatic HER2-positive BC who had prior taxane and trastuzumab treatment. ⁷⁵ Pyrotinib+capecitabine achieved significantly longer PFS (median 11.1 versus 4.1 months; p <0.001); however, this trial did not enroll patients with untreated, symptomatic BM. Two phase II trials [ClinicalTrials.gov identifiers: NCT03691051, NCT03933982] have been initiated to investigate the antitumor activity of pyrotinib on BM (Table 3).

In January 2020, a phase I/II study of epertinib in refractory metastatic HER2-positive including BM BC reported that combination of epertinib with trastuzumab±capecitabine had promising antitumor activity with favorable toxicity profiles. ⁷⁶ These results encourage more studies to investigate new HER2-directed combination therapies.

Other innovative molecular-targeted therapy

Based on the advances in the understanding of the underlying mechanisms of BC and BM, several molecular-targeted therapies have been developed in the last decade and have become some of the main therapeutic interventions for metastatic BC.

Bevacizumab, a humanized vascular endothelial growth factor (VEGF) monoclonal antibody, is thought to transiently normalize peritumoral vessels, resulting in enhanced drug delivery to BM. ⁷⁷ The following three phase II trials attempted to demonstrate this hypothesis using a combination of bevacizumab and other cytotoxic agents. Thirty-eight patients with progressive BM were assigned to bevacizumab on day 1 of a 3-week cycle, followed by carboplatin and trastuzumab if HER2-positive on day 8 of one cycle and day 1 of subsequent cycles. ⁷⁸ CNS ORR by composite criteria and RECIST was 63% and 45%, respectively. A second study in patients with WBRT-refractory BM investigated bevacizumab followed by etoposide and cisplatin (BEEP) with a 1-day window period. ⁷⁹ Notably, this treatment schedule achieved a high CNS ORR according to the volumetric criteria of 77.1%, and 54.3% by RECIST. A third study [ClinicalTrials.gov identifier: NCT01281696] tested a similar regimen and included patients with leptomeningeal seeding, who would be treated with intrathecal methotrexate (Table 3). Pilot studies showed promising efficiency in leptomeningeal seeding patients. ⁸⁰ Additional investigation is needed to optimize the proper treatment period and chemotherapeutic agent combination.

Cabozantinib is a small, multiple TKI that inhibits MET and VEGF receptor-2, penetrates into the CNS, and has significant antitumor activity for BM in non-small cell lung cancer and renal-cell carcinoma.^81,82 In patients with heavily pretreated BM in BC, cabozantinib was well tolerated but did not show sufficient CNS response [CNS ORR (per RECIST 1.1) 5.6%], ⁸³ in contrast with the previous studies showing higher CNS ORR after anti-VEGF.^78,79 Therefore, further investigations are needed to find out more detailed antitumor mechanisms underlying the VEGF pathway of BM from BC, which could explain the different antitumor activities of these two agents.

Another treatment strategy actively being investigated is inhibition of the phosphoinositide-3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway. Hyperactivation of this pathway is a mechanism of trastuzumab resistance. ⁸⁴ A phase II study, LCCC 1025, investigated whether inhibition of PI3K/mTOR and HER2 might lead to more significant responses in patients with HER2-positive BM. ⁸⁵ Everolimus, a small molecule of the mTOR complex 1 inhibitor, was given with trastuzumab and vinorelbine; the intracranial response rate was very low (4%) and only one patient experienced a partial response. However, a similar time to progression and OS as previous studies, and a clinical benefit rate of 65% at 6 months, indicated further research is needed. Several agents targeting PI3K, such as BKM120 [ClinicalTrials.gov identifier: NCT02000882] and GDC-0084 [ClinicalTrials.gov identifier: NCT03765983], are currently under investigation (Table 3). One thing to note is that PI3K inhibitors crossing the BBB have been reported to cause mood alterations.^86,87 In a phase I, dose-escalation study, 20% of all patients experienced altered mood, suspected to be related with BKM120. ⁸⁷ Therefore, investigators of PI3K trials should pay attention to the psychological toxicities and monitor them properly.

Cyclin-dependent kinase (CDK) 4/6 inhibitors have been developed, especially focusing on hormone receptor (HR)-positive/HER2-negative metastatic BC, and have significantly improved PFS in these populations.^88–90 However, previous clinical trials of CDK4/6 inhibitors excluded patients with CNS metastasis or included patients with pretreated and stable BM, demonstrating limited evidence of their CNS efficacy. ⁹¹ In a phase II study, abemaciclib, one of the CDK4/6 inhibitors, showed an intracranial clinical benefit of 25% among 58 patients with heavily pretreated BM from HR-positive/HER2-negative BC. ⁹² In HER2-positive and TNBC, the use of CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib, etc.) in metastatic settings with or without untreated BM, are currently under investigation. ⁹³ Disappointingly, a phase II study [ClinicalTrials.gov identifier: NCT02774681] of palbociclib in patients with HER2-positive BM was terminated due to slow accrual.

In TNBC, poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors have been of interest. TBCRC 018 demonstrated that iniparib+irinotecan showed a slight benefit of time to progression in patients with progressive TNBC BM. ⁹⁴ However, iniparib is not currently considered a bona fide PARP inhibitor. ⁹⁵ Other PARP inhibitors, olaparib and veliparib, are currently not candidates for the treatment of BM. A case report demonstrated the potential role of olaparib in BM, ⁹⁶ while a phase II study [ClinicalTrials.gov identifier: NCT02595905], including BM patients, has been initiated to investigate cisplatin with or without veliparib.

Return of classic chemotherapy

One approach for facilitating penetration of chemotherapeutic agents through the BBB for BM treatment is to modify their structures through conjugation with a peptide vector or via pegylation. ⁹⁷ ANG1005 (GRN1005) makes Angiopep-2, a peptide vector that facilitates paclitaxel transport into the CNS. ⁹⁸ Importantly, ANG1005 showed no CNS toxicity in a phase I trial. ⁹⁹ In addition, a phase II study of ANG1005 in patients with recurrent BM showed excellent antitumor activity in intracranial and extracranial lesions. ¹⁰⁰ A phase II trial [ClinicalTrials.gov identifier: NCT01480583] testing ANG1005 (+trastuzumab, if HER2 positive) was completed, but results are not available (Table 3). Other randomized trials are being pursued to validate this novel agent.

Etirinotecan pegol (NKTR-102), the prodrug of irinotecan, is a novel long-acting topoisomerase-I inhibitor, consisting of a four-arm polyethylene glycol with one irinotecan at the end of each arm. ¹⁰¹ It slowly hydrolyzes in vivo, and continuously produces SN38, the active irinotecan metabolite, which prevents high plasma concentrations of irinotecan and SN38, as well as unwanted side effects. ¹⁰² The phase III BEACON trial assessed the superiority of etirinotecan pegol to the currently available TPC in patients with locally recurrent or metastatic BC, who had prior treatment with an anthracycline, a taxane, and capecitabine. ¹⁰³ Patients were randomized to etirinotecan pegol or single-drug TPC (one of: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). This trial failed to show an OS improvement in the etirinotecan pegol arm, but in the subgroup analysis of OS, patients with BM had superior OS (median 10 versus 4.8 months) with an HR of 0.51 (95% CI 0.30–0.86). ¹⁰⁴ Although a small number of patients with BM were included in this analysis, the survival benefit of etirinotecan pegol was clear with favorable safety. Based on these results, another phase III trial in this population with BM (ATTAIN) [ClinicalTrials.gov identifier: NCT02915744] is underway (Table 3).

Tesetaxel is of the taxane class of drugs, with an advantage of oral administration. In phase II study with locally advanced or metastatic HER2-negative and HR-positive BC patients, tesetaxel showed significant activity as a single agent, with an ORR per RECIST 1.1 of 45% (95% CI 29–62). ³⁰ Tesetaxel with or without capecitabine is being investigated in the randomized phase III study, CONTESSA [ClinicalTrials.gov identifier: NCT03326674], for these patients. CONTESSA TRIO [ClinicalTrials.gov identifier: NCT03952325] is a two-cohort, phase II study of tesetaxel. In Cohort 1, patients with locally advanced or metastatic TNBC will be randomized to tesetaxel or three inhibitors of programmed cell death-1 (PD-1) or its ligand (PD-L1; nivolumab, pembrolizumab, or atezolizumab). In Cohort 2, elderly patients (⩾65 years old) with HER2-negative locally advanced or metastatic disease will receive tesetaxel monotherapy. In this study, stable or progressing CNS metastases, excluding leptomeningeal disease are permitted but not required.

Establishing the efficacy of existing drugs against BM is as important as development of new agents. In a phase II trial, epothilone B did not achieve prespecified efficacy criteria, but increased diarrhea. ¹⁰⁵ In addition, a recent article suggested that irinotecan+temozolomide could be a treatment option for progressing CNS diseases. ¹⁰⁶ Eribulin mesylate, an approved agent for metastatic BC, is being tested in phase II trials [ClinicalTrials.gov identifier: NCT02581839 and NCT03412955; Table 3] for BM. A temozolomide and T-DM1 combination is being evaluated in a recruiting phase I/II study in patients with HER2-positive BM with prior local treatment [ClinicalTrials.gov identifier: NCT03190967; Table 3).

Prospects of immunotherapy

Over the past several years, the most revolutionary advancement in cancer treatment has been the discovery of immune-checkpoint inhibitors (ICIs). A mechanism of tumor survival and metastasis is activation of the immune-checkpoint pathway to induce immunosuppressive conditions; ¹⁰⁷ ICI blocks this activation, thereby increasing immune-mediated tumor cell killing. After approval of ipilimumab, which targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), for advanced melanoma treatment in 2011, several immunotherapeutic monoclonal antibodies have been developed to interrupt PD-(L)1 and CTLA-4 activity and have antitumor activity. The efficacy of immunotherapy in BM is well established in melanoma, non-small cell lung cancer, and renal-cell carcinoma (Table 4). Importantly, a review by Di Giacoma illustrated that intracranial ORR in melanoma was 5–26% with ICI monotherapy and 46–55% with ICI combination, suggesting that future studies should focus on the synergism of ICI-based therapeutic combinations (Table 4). ¹⁰⁸

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Table 4.

Prospective trials of immunotherapy for patients with brain metastases from other solid tumors.

Immune-checkpoint inhibitor	Primary tumor	Population characteristics	Phase	Intracranial ORR	Overall survival	References
Atezolizumab	NSCLC	Asymptomatic supratentorial BM (n = 85)	III	Not reported	Median: 20.1 months	Rittmeyer et al. 109
Ipilimumab	Melanoma	Cohort A: asymptomatic BM (n = 51)Cohort B: symptomatic BM (n = 21)	II	(mWHO, irORR)Cohort A: 16%Cohort B: 5%	Median/2 yearsCohort A: 7 months/26%Cohort B: 4 months/10%	Margolin et al. 110
Ipilimumab+fotemustine	Melanoma	Asymptomatic BM (n = 20)	II	(irORR)30%	Median: 12.7 months2 years: 39%3 years: 28%	Di Giacomo et al.111,112
Ipilimumab+nivolumab	Melanoma	Cohort A: asymptomatic BM (n = 101)Cohort B: symptomatic BM (n = 18)	II	(modified RECIST)Cohort A: 55%Cohort B: 17%	Median: not reached6 months: 92%9 months: 83%	Tawbi et al.113,114
	Melanoma	Cohort A: asymptomatic, untreated BM (n = 35)	II	(modified RECIST)46%	Median: not reached6 months: 78%	Long et al. 115
	RCC	Asymptomatic, untreated BM (n = 28)	III/IV	(RECIST 1.1)29%	Median: not reached	Emamekhoo et al. 116
Nivolumab	Melanoma	Cohort B: asymptomatic, untreated BM (n = 25)Cohort C: symptomatic BM or local therapy failed BM or LMS (n = 16)	II	(modified RECIST)Cohort B: 20%Cohort C: 6%	Median/6 monthsCohort B: 18.5 months/68%Cohort C: 5.1 months/44%	Long et al. 115
	NSCLC	Treated stable BMCheckMate 063 (n = 3), 017 (n = 9), and 057 (n = 34)	NA *	(RECIST 1.1)PR+SD: 33%	MedianCheckMate 017: 5.0 monthsCheckMate 057: 7.6 months	Goldman et al. 117
	RCC	Asymptomatic BM, progressive after VEGFR-directed therapyCohort A: untreated BM (n = 39)Cohort B: treated BM (n = 34)	II	(RECIST 1.1)Cohort A: 12%Cohort B: 0%	1 yearCohort A: 67%Cohort B: 59%	Flippot et al. 118
Pembrolizumab	Melanoma	Asymptomatic, untreated BM (n = 23)	II	(RECIST 1.1)26%	Median: 17 months2 years: 48%	Kluger et al. 119
	NSCLC	Active BMCohort 1: PD-L1 positive (n = 34)Cohort 2: PD-L1 negative or unevaluable (n = 5)	II	(modified RECIST)Cohort 1: 30%Cohort 2: 0%	Median/1 year/2 yearsCohort 1: 9.9 months/40%/34%	Goldberg et al.120,121

*

Pooled analysis of the three prospective trials: CheckMate 063 (phase II), 017 (phase III), and 057 (phase III).

BM, brain metastasis; irORR, immune-related objective response rate; LMS, leptomeningeal seeding; mWHO, modified World Health Organization criteria; NA, not applicable; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PD-L1, programmed cell-death ligand 1; PR, partial response; RCC, renal-cell carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease; VEGFR, vascular endothelial growth factor receptor.

In metastatic TNBC, atezolizumab, a monoclonal antibody against PD-L1, in combination with nab-paclitaxel, was approved recently as first-line therapy based on the results of the IMpassion 130 trial. In this randomized phase III trial, 902 patients with untreated metastatic TNBC were assigned to receive atezolizumab or placebo, combined with nab-paclitaxel. ¹²² Addition of atezolizumab to nab-paclitaxel significantly improved PFS compared with placebo (median 7.2 versus 5.5 months; HR 0.80, 95% CI 0.69–0.92; p = 0.002). Median OS was longer in the atezolizumab+nab-paclitaxel group (21.3 months) than in the placebo+nab-paclitaxel group (17.6 months; p = 0.08). Although subgroup analysis showed no PFS benefit in patients with BM, approximately only 7% of patients in each arm had BM, and combined chemotherapy was not optimal for CNS metastases. Future clinical trials of atezolizumab might be designed to evaluate clinically meaningful benefit in patients with BM from TNBC.

Another randomized phase III study, the KEYNOTE-355 trial [ClinicalTrials.gov identifier: NCT02819518], was released in a press in February 2020. ¹²³ This trial recruited patients with locally recurrent unresectable or metastatic TNBC, not previously treated with chemotherapy, and did not exclude patients with BM if they were treated and stable. This study consisted of two parts: in part one, pembrolizumab, an anti-PD-1, was administered with one of three chemotherapeutic agents chosen by investigators (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin); in part two, 847 patients were randomized to receive pembrolizumab or placebo, in combination with one of the three chemotherapy regimens. The interim analysis demonstrated that pembrolizumab with chemotherapy significantly improved PFS compared with the placebo group (i.e. chemotherapy alone) in patients with a PD-L1 combined positive score of ⩾10 tumors. This trial continues to assess OS, the other primary endpoint.

Currently, other randomized phase III studies using pembrolizumab [ClinicalTrials.gov identifier: NCT02555657] and atezolizumab [ClinicalTrials.gov identifier: NCT03125902] in metastatic TNBC have been initiated. However, these trials exclude active CNS metastases, and are therefore unable to address the efficacy of ICIs on BM. We summarize the currently available prospective trials of ICI for patients with BM from other solid tumors in Table 4.

A systematic review of 13914 patients found the highest incidence of tumor-infiltrating lymphocytes of at least 50% both in TNBC (20%, range 4–37%) and HER-2 positive BC (16%, range 11–24%), ¹²⁴ suggesting that proper modulation of the tumor microenvironment could boost antitumor activity of ICIs. Recent approaches have focused on the role of RT in this process, discussed further in the following.