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Purpose:A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC.Patients and Methods:In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers.Results:Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders.Conclusions:The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

Supplementary Table from A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer

Supplementary Figure from A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer

Characteristics of TBCRC023 Patients with disease progression

Purpose:Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR.Patients and Methods:TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2-positive breast tumors measuring ≥2 cm (median = 5 cm) were randomized in a 1:2 ratio to 12 versus 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was administered in patients whose tumors were also estrogen receptor (ER) positive. All evaluable patients were assessed for in-breast pCR.Results:Ninety-seven patients were enrolled (33 in 12-week arm and 64 in 24-week arm), of whom 94 were evaluable. Median age was 51 years, and 55% were postmenopausal. Median tumor size was 5 cm, and 65% were ER-positive. The rate of pCR in the 24-week arm was 28% and numerically superior to the 12-week arm (12%). This was driven by increased pCR in the ER-positive subgroup (33% vs. 9%). Study treatment was well tolerated, with grade 1–2 diarrhea and acneiform rash being the most common toxicities.Conclusions:Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from deescalation of therapy.

Treatment discontinuation in TBCRC023 Patients

BACKGROUND Metaplastic breast cancer (MpBC) is an extremely rare, therapeutically recalcitrant and aggressive variant of triple negative breast cancer (TNBC). We have previously shown molecular alterations in inducible nitric oxide (iNOS) signaling in MpBC is associated with worse overall survival. Preclinical models have shown pan-NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) reduces tumor growth and epithelial to mesenchymal transition in mesenchymal cell lines. We have also previously shown in TNBC patients treated with LNMMA and docetaxel, the non-responders have a higher expression of M2 macrophage vs the responders have decreased pro-tumor N2 neutrophils at the end of therapy. Here, we report the results of L-NMMA plus taxane in a cohort of MpBC patients. METHODS We conducted a phase 1B/2 trial, with L-NMMA (starting dose of 7.5 mg/kg which was escalated to recommended phase 2 dose of 20 mg/kg) and docetaxel (100 mg/m2) every 3 weeks. Daily amlodipine was given to prevent hypertension from L-NMMA. Primary objective was to assess clinical benefit rate (CBR), as assessed by the Response Evaluation Criteria in solid tumors (RECIST). Secondary objectives were to study overall response rate (ORR), progression free survival (PFS), overall survival (OS), dose limiting toxicities (DLT), response correlation with type of MpBC, body mass index (BMI) and ethnicity. Exploratory analysis included immune correlates for clinical response; staining for iNOS, M2 macrophages (CD 68, CD 163), N2 neutrophils (CD 15, arginase), immune infiltration (PD-L1, CD 8) and fibrosis marker (α- SMA). Fisher’s exact test was used to find the association between different patient’s characteristics and the main outcome. A p-value of 0.05 was considered statistically significant and all analyses were conducted using Stata V16.1 (StataCorp, College Station, Texas 77845 USA) RESULTS Of the total 35 TNBC patients recruited, 15 patients had MpBC (Phase 1B, n= 4; Phase 2, n=11); 86.6% (13/15) patients had metastatic breast cancer (MBC), with a median of 2 prior lines of therapy (range 0-5) and 13.3% (2/15) had anthracycline-refractory locally advanced breast cancer (LABC). The CBR was 40% (6/15); the ORR was 20% (3/15) with 1 PR in MBC , 1 pathological CR and 1 PR in LABC. Grade 3 or more toxicity was seen in 13.3% (2/15) patients; however, none was attributed to L-NMMA. The mPFS and mOS for MBC patients were 4.5 months (range 3-7m) and 12.8 months, respectively. The response was more likely to be in women of Caucasian ethnicity, BMI> 25 and non-spindle pathological features such as squamous differentiation, keratinized and myxo-chondroid tumors; albeit these were not statistically significant (Table 1). CONCLUSIONS Inhibition of iNOS pathway in MpBC is a promising and novel therapeutic option in this very challenging breast cancer subtype. The small study size is an impediment in identifying clinical factors which can predict a response. This warrants further evaluation of treatment with L-NMMA in chemo-refractory MpBC patients in a larger clinical trial. Table 1.Association between ethnicity, BMI and pathological characteristics with responseTotalNo responderResponderp-valueN=13N=7N=6Ethnicity0.19Caucasian10 (76.92%)4 (57.14%)6 (100.00%)Other3 (23.08%)3 (42.86%)0 (0.00%)Obesity1.00=25 BMI10 (76.92%)5 (71.43%)5 (83.33%)Pathological features0.27Spindle5 (38.46%)4 (57.14%)1 (16.67%)Other8 (61.54%)3 (42.86%)5 (83.33%)Data are presented as n (%). *P-value from Fisher’s exact test. The 2 patients with adverse events were excluded from the analysis. Citation Format: Akshjot Puri, Adriana Ordonez, Ann C. Anselme, Liliana Guzman, Polly Niravath, Jenny C. Chang. Phase 1B/2 clinical trial targeting nitric oxide in the treatment of chemo-refractory metaplastic triple-negative breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-07.

Purpose: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. Patients and Methods: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. Results: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. Conclusions: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

PURPOSE Leptomeningeal disease (LMD) is an aggressive complication of metastatic breast cancer (MBC) with brain metastases (BM), with a short survival of weeks to months. Studies suggest that surgical resection of BM may increases the risk of LMD, especially in infratentorial metastases. In this retrospective study, we examine this and other factors which may be associated with increased risk of LMD. METHODS A database search at a single institution identified 178 patients with MBC and treated BM between 2007-2020. We collected demographic, clinical, radiographic and other treatment data. LMD was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. Cox proportional hazards model was used. RESULTS After a median follow up of 8.5 months, 41 out of 178 patients (23%) with BM developed LMD. Median time to develop LMD was 130 days. Mean age was 51.3 years. The number and size of the BM, hemorrhagic/cystic lesions, progressive/stable systemic disease, and extracranial metastases sites other than liver did not pose a higher risk of LMD. Infratentorial lesions (HR=5.41) and liver metastases (HR=2.28) had a higher risk of LMD. Patients who had any surgery did not have a higher risk for LMD (HR 1.13). The LMD group had a worse overall survival as compared to the non-LMD group. CONCLUSIONS Among MBC patients with BM, infratentorial BM and visceral liver lesions increase the risk of LMD whereas local treatment modalities such as surgery and radiation do not. This data implies that local treatment strategy should not differ based on potential risk for LMD.

Leptomeningeal metastases (LM) are an aggressive complication of metastatic breast cancer (MBC) with brain metastases (BM), with a short survival of weeks to months. Studies suggest that surgical resection of BM may increase the risk of LM, especially in infratentorial metastases. In this retrospective study, we examine this and other factors which may be associated with increased risk of LM.A database search at a single institution identified 178 patients with MBC and treated BM between 2007 and 2020. We collected demographic, clinical, radiographic, and other treatment data. LM was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. Cox proportional hazards model was used.After a median follow-up of 8.5 months, 41 out of 178 patients (23%) with BM developed LM. Median time to develop LM was 130 days. Mean age was 51.3 years. The number and size of the BM, hemorrhagic/cystic lesions, progressive/stable systemic disease, and extracranial metastases sites other than liver did not pose a higher risk of LM. Infratentorial lesions (HR = 5.41) and liver metastases (HR = 2.28) had a higher risk of LM. Patients who had any surgery did not have a higher risk for LM (HR 1.13). The LM group had a worse overall survival as compared to the non-LM group.Among MBC patients with BM, infratentorial BM and visceral liver lesions increase the risk of LM, whereas local treatment modalities such as surgery and radiation do not. These data imply that local treatment strategy should not differ based on potential risk for LM.

Anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) syndrome is a very rare condition that is most commonly associated with breast and gynecologic cancers. Those cases associated with breast cancer tend to be human epidermal growth factor receptor 2 (HER2)-positive, though the reason for this correlation is unknown. Most commonly, the neurologic symptoms of the PCD syndrome predate the patient’s cancer diagnosis. Thus, prompt diagnosis of PCD is essential to allow for early treatment of the neurologic symptoms and the underlying malignancy. However, the prognosis is very poor for the anti-Yo-associated paraneoplastic syndrome, since neurologic damage is usually rapid and irreversible. Further progression may be stopped with appropriate treatment of cancer, but existing neurologic deficits at the time of diagnosis are usually permanent. Steroids, plasma exchange, and rituximab are commonly used treatments, though these have had mixed to poor results.

Half of hormone receptor-positive (HR+) breast cancer patients will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treatment for AIA, there has been some evidence to support high-dose vitamin D as a treatment.We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vitamin D3 (800 IU daily for 52 weeks), or high-dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). The primary end point was development of AIA. The trial was designed to enroll 184 patients. This futility analysis was performed after 93 patients were enrolled.The high-dose vitamin D regimen was effective in raising serum vitamin D levels, but there was no significant difference in development of AIA between the two arms. In the high-dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard-dose arm. The planned futility analysis was positive; thus, the study was terminated. Neither baseline vitamin D nor 12-week vitamin D level was predictive of AIA development.Although vitamin D levels were increased in the high-dose arm, there was no significant signal for benefit of high-dose vitamin D supplementation for AIA prevention in this unblinded trial. This study, along with several others, implies that vitamin D likely does not play a significant role in AIA for the majority of patients.