Pertuzumab In HER2-positive Breast Cancer Research Articles

Abstract PO3-19-01: A Randomized Controlled Trial of Metastasis-directed Therapy for Oligometastases in Breast Cancer (OLIGAMI trial; JCOG2110)

Abstract Background: Oligometastases were initially described as a concept bridging localized disease with widespread distant metastases, but a consensus on its definition has yet to be reached. Recently, the term "metastasis-directed therapy" (MDT) was coined to encompass local therapy for distant metastases, including surgery and radiation therapy (RT), especially stereotactic body radiation therapy (SBRT). Though OLIGO-BC1 and SABR-COMET have indicated the potential benefits of MDT for oligometastases, NRG-BR002 revealed no significant difference in progression-free survival (PFS). As a definitive conclusion to this clinical question has not been reached, there is an increasing demand for phase III trials focusing on breast cancer (BC). We planned the JCOG2110, also called as OLIGAMI trial . Design: OLIGAMI trial is a multi-institutional, two-arm, open-label, randomized controlled phase III trial being conducted with the participation of 50 hospitals belonging to Japan Clinical Oncology Group. After the first registration, all patients will be performed in a 12-week, subtype-specific, systemic therapy consisting of CDK4/6 inhibitors with hormonal therapy for luminal BC, docetaxel with trastuzumab and pertuzumab for HER2-positive BC, chemotherapy with immune checkpoint inhibitors for triple-negative BC expressing PD-L1, and olaparib for cases harboring BRCA mutations. For other triple-negative BC, chemotherapy will be administered. If this 12-week systemic therapy dose not cause any progression or complete response, patients proceed to second registration for randomization; arm A continues same systemic therapy alone, and arm B performs MDT followed by same systemic therapy. The MDT will involve either RT or surgery, and RT will involve mainly SBRT and partly conventional RT. Eligibility criteria: OLIGAMI trial will encompass all subtypes of advanced BC. The key criteria of the first registration are as follows: 1) Histologically diagnosed as invasive BC. Biopsy from oligometastases is desirable but not required. 2) Diagnosed with advanced BC with oligometastases by neck to pelvis enhanced CT, FDG-PET, and brain enhanced MRI. 3) Oligometastases defined as: (i) Maximum diameter of each tumor is 3 cm or less. (ii) Total number of 3 or less. (iii) In case of brain metastasis, maximum diameter is 2 cm or less and asymptomatic. 4) The patient with local recurrence is included. 5) De novo stage IV BC is included. The criteria of secondary registration are as follows: 1) The planned number of courses of systemic therapy has been performed. 2) No progression or new distant metastasis by response evaluation. 3) At least one oligometastaseis remains. Specific Aims: OLIGAMI trial aims to confirm the superiority of MDT to systemic therapy for oligometastases of BC. The primary endpoint is overall survival (OS) after randomization, while the secondary endpoints include OS after first registration, PFS, progression site (oligometastases vs. non-oligometastases), PFS specifically related to MDT (restricted arm B), proportion of adverse events and serious adverse events, and the non-progression proportion of health-related quality of life. Statistical methods: The sample size was calculated as 268 to detect 12% of 5-year OS difference with one-sided alpha of 0.05, power of 70%, 3 years of accrual, and 5 years of follow up. Therefore, we assumed the planned sample size for second registration for randomization as 270. We set the number of first registration as 340, assuming that there may be some patients with progression or complete response after the systemic therapy for 12 weeks. Present accrual and target accrual: The patient accrual will start in August 2023. Enrolment of 340 patients for first registration is planned over a 3-year accrual period. Contact information: Principal investigator, Toshiyuki Ishiba, MD. Ph.D. ishiba0313@gmail.com Citation Format: Toshiyuki Ishiba, Ikuno Nishibuchi, Fumitaka Hara, Keita Sasaki, Ryo Sadate, Yuta Sekino, Ryunosuke Machida, Haruhiko Fukuda, Takahiro Kogawa, Tomomi Fujisawa, Yasuaki Sagara, Yoichi Naito, Kaori Terata, Yukinori Ozaki, Akihiko Shimomura, Takehiko Sakai, Chizuko Kanbayashi, Tsuguo Iwatani, Hideo Shigematsu, Kenji Tamura, Takashi Mizowaki, Michio Yoshimura, Naoto Shikama, Tadahiko Shien, Hiroji Iwata. A Randomized Controlled Trial of Metastasis-directed Therapy for Oligometastases in Breast Cancer (OLIGAMI trial; JCOG2110) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-01.

Benefit of postoperative regional nodal irradiation in patients receiving preoperative systemic therapy with docetaxel/carboplatin/trastuzumab/pertuzumab for HER2-positive breast cancer

AimThe role of regional nodal irradiation (RNI) after preoperative systemic treatment (PST) with targeted therapy for HER2-positive breast cancer remains uncertain. This study aimed to investigate the impact of RNI on locoregional recurrence (LRR) and disease-free survival (DFS) outcomes after docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) for PST. MethodsWe retrospectively analyzed 255 patients who were treated with six cycles of TCHP between 2016 and 2019. The patients were divided into four groups based on clinical nodal involvement: group A, with no nodal disease; group B, with axillary lymph node (AXL) level I; group C, with AXL level I with II/III; and group D, with supraclavicular or internal mammary nodes. ResultsThe RNI group had more advanced nodal disease (C/D) than the no RNI group (56.9 % vs. 6.8 %). With a median follow-up of 51.3 months, there were two (0.8 %), three (1.2 %), and 15 (5.9 %) local, regional, and distant metastases, respectively. LRR did not differ significantly according to the RNI (2.6 % vs. 1.0 %, p = 0.651). Group D had the most frequent distant metastases (17.5 %; p = 0.005). The 4-year DFS rate was 92.7 %, and DFS did not improve significantly after RNI (p = 0.074). When stratified by clinical nodal groups and pathological axillary response, RNI had no effect on LRR/DFS outcomes. ConclusionWith a rare incidence of LRR, RNI did not significantly affect LRR or DFS in patients with HER2-positive breast cancer after with PST-TCHP. However, intensive systemic treatment is required for advanced diseases (C/D). Selective de-intensified RNI and intensified systemic treatment should be investigated in future studies.

Efficacy and safety of treatment with or without pertuzumab for HER2-positive breast cancer: A meta-analysis.

We conducted a meta-analysis to systematically evaluate the efficacy and safety of treatment with or without pertuzumab for human epidermal growth factor receptor-2 -positive (HER2)-positive breast cancer and provided evidence-based reference for clinical use. The Cochrane Library, PubMed, EMbase, Clinical Trials and Web of Science databases were searched for studies published up to July 2022, which reported clinical randomized controlled trials of treatment in combination with pertuzumab (experimental group) and without pertuzumab (control group) for HER2-positive breast cancer. Meta-analysis was performed using R 4.2.1 based on the extraction of the data and the risk of bias assessment under the supervision of the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. The results from this study showed that, the patients in the experimental group showed prolonged progression-free survival [hazard ratio = 0.72, 95% confidence interval (CI) (0.65,0.80), P < .01] and overall survival [hazard ratio = 0.80, 95% CI (0.66,0.96), P = .02] than those in the control group. In terms of safety, the incidence of grade ≥ 3 adverse events including diarrhea [risk ratio (RR) = 2.36, 95% CI (1.98,2.81), P < .01] and anemia [RR = 1.43, 95% CI (1.17,1.75), P < .01] in the experimental group were significantly higher than those in the control group. The incidence of common adverse events, that is rash in the experimental group was significantly higher than that in the control group [RR = 1.62, 95% CI (1.38,1.90), P < .01]. These results support that the treatment in combination with pertuzumab is superior to the treatment in combination without pertuzumab in the treatment of HER2-positive breast cancer, but there are some adverse effects such as diarrhea, anemia, and rash, which should be carefully monitored in clinical practice.

Safety and tolerability of subcutaneous trastuzumab and intravenous pertuzumab as adjuvant treatment for HER2 positive breast cancer: a pilot study

BackgroundSubcutaneous (SC) trastuzumab is similar to intravenous trastuzumab in terms of pharmacokinetics, efficacy and tolerability. The use of dual anti-HER2 agents trastuzumab and pertuzumab has become the new standard for...

Concordance of multispectral immunofluorescence (mIF) with programmed death ligand 1 (PD-L1) and stromal tumor infiltrating lymphocyte (sTILs) clinical assays in early-stage breast cancer (BC).

e12589 Background: There is growing need for surrogate immune-based biomarkers in BC to enhance prediction accuracy and to facilitate comparisons of therapeutic activity in the context of clinical trials. We report mIF as a high-dimensional biomarker that is highly concordant with both PD-L1 (SP142) and sTIL clinical assays (H&amp;E), but with greater precision to quantify on-treatment pharmacodynamic effects. We also demonstrate how statistical modeling can be employed to improve precision of PD-L1/sTIL estimates, and reduce sample size requirements for biomarkers-driven comparative clinical trials. Methods: Samples were obtained from a recently-reported pre-surgical cytokine-based phase Ib immunotherapy (IRX-2) clinical trial (NCT02950259). Pre-treatment and resection tissues (n = 30) were analyzed for sTIL score, PD-L1 status, and mIF (PerkinElmer Vectra) using antibodies to quantify BC cells (cytokeratin), immune cells (CD3, CD8, CD163, FOXP3), and per-cell PD-L1 expression. Mixed effects regression models were employed to correct for intratumoral heterogeneity and enhance statistical precision. Monte Carlo simulations were employed to evaluate whether regression modeling could reduce sample size required to detect treatment-related increases in sTIL/PD-L1 in pre-surgical clinical trials. Results: Results: mIF sTIL estimates were highly correlated with H&amp;E sTIL score (pre-treatment samples: r = 0.59, p &gt; 0.001; excisional samples: r = 0.63, p &gt; 0. 001). mIF PD-L1 estimates were highly correlated with the PDL1 SP142 assay, with average densities increasing concordantly according to SP142 IC category (IC0 v. IC1, p = 0.04; IC0 v. IC2/3, p = 0.003). Our regression modeling approach dramatically improved power to demonstrate treatment-related changes in sTIL and PD-L1. The estimated sample size requirement to show the observed effect on sTIL score (1.80 fold change, CV 0.83) was n = 25 with conventional t-testing of means, versus n = 13 with regression modeling. Conclusions: mIF is concordant with SP142 and sTIL prognostic assays, but with increased precision to quantify treatment related changes. Regression modeling can dramatically improve the utility of mIF as a surrogate immune-based biomarker. Our approach is being utilized in ongoing phase II studies to compare the activity of pembrolizumab +/- locoregional cytokines (IRX-2) in triple negative BC, and paclitaxel/trastuzumab +/- pembrolizumab +/- pertuzumab in HER2-positive BC.

Efficacy and safety of HER2 inhibitors in combination with or without pertuzumab for HER2-positive breast cancer: a systematic review and meta-analysis

BackgroundAlthough the dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab and docetaxel, has shown promising results in HER2+ breast cancer patients, whether the dose, efficacy and safety of this treatment differs from those of other pertuzumab-based dual anti-HER2 therapies remain controversial. This systematic review evaluates the efficacy and safety of H (trastuzumab or trastuzumab emtansine ± chemotherapy) + P (pertuzumab) compared with those of H in HER2+ breast cancer patients.MethodsA comprehensive search was performed to identify eligible studies comparing the efficacy and safety of H + P versus H. The pathologic complete response (pCR), median progression-free survival (PFS) and overall survival (OS) were the primary outcomes, and safety was the secondary outcome. A subgroup analysis of pCR according to hormone receptor (HR) status was performed. All analyses were conducted using STATA 11.0.ResultsTwenty-six studies (9872 patients) were identified. In the neoadjuvant setting, H + P significantly improved the pCR [odds ratio (OR) = 1.33; 95% confidence interval (CI), 1.08–1.63; p = 0.006]. In the metastatic setting, H + P significantly improved PFS [hazard ratios (HRs) = 0.75; 95% CI, 0.68–0.84; p < 0.001]. There was a trend towards better OS but that it did not reach statistical significance (HRs = 0.81; 95% CI, 0.64–1.03; p = 0.082). A subgroup analysis revealed that the HER2+/HR- patients who received H + P showed the highest increase in the pCR. Rash, diarrhea, epistaxis, mucosal inflammation, and anemia were significantly more frequently observed with H + P than with H, whereas myalgia was less frequent (OR = 0.91; 95% CI, 0.82–1.01; p = 0.072), and no significant difference in cardiac toxicity was observed between these therapies (OR = 1.26; 95% CI, 0.81–1.95; P = 0.309).ConclusionsOur study confirms that H + P is superior to H in the (neo)adjuvant treatment of HER2+ breast cancer, and increase the risk of acceptable and tolerable toxicity (rash, diarrhea, epistaxis, mucosal inflammation, and anemia).Trial registrationA systematic review protocol was registered with PROSPERO (identification number: CRD42018110415).

Retrospective single-center outcome analysis of neoadjuvant and palliative treatment with dual trastuzumab and pertuzumab in HER2-positive breast cancer.

e12114 Background: Her2-positive (Her2pos) breast cancer (BCa) is the second most lethal subtype of BCa. The treatment of Her2-positive BCa was revolutionized due to the dual use of trastuzumab and pertuzumab (T+P) in recent years both in the neoadjuvant and the palliative setting. Although several years have passed after initial approval of these drugs, single-center outcome data as reported by clinicians is sparse. In this retrospective study, we set to assess outcomes measures at our institution, Austria’s largest academic hospital, for the use of T+P in early and metastasized BCa. Methods: We acquired records on combined pertuzumab and trastuzumab orders from our intramural drug order software (CATO, Cato Research, Durham, NC, USA) for the time period of May 2013 to March 2018. Further, using electronic patient histories, we described both the neoadjuvant and palliative patient groups by assessment of body weight/size, tumor stage, histology including immunohistochemistry (IHC), lines of oncological therapies received, ejection fraction (EF) drops&gt;10%, deaths and most importantly the outcomes measures pathological complete response (pCR, neoadjuvant cohort) rate and progression-free survival (PFS, palliative cohort). Results: 120 breast cancer patients were given dual therapy with T+P. The neoadjuvant cohort contained 63 patients, while the palliative cohort included 57 patients. All patients included were female. Full histology including IHC data was available for 47 of 63 patients in the neoadjuvant cohort and 30 of 57 patients in the palliative cohort. BMI was 25.6 and 23.3, respectively, on average. The mean age was 54 years in the neoadjuvant and 56 years in the palliative cohort. 73.6% (39/53) and 65.9% (29/44) of tumors were ER positive as determined by IHC. While neoadjuvant patients obtained an average of 6.5 cycles, patients within the palliative cohort received a mean of 17.3 cycles of T+P. 0 and 17 deaths were observed in the respective cohorts. Data on pCR and PFS was available for 95.2% and 91.2% of patients, respectively. The pCR rate within the neoadjuvant cohort was 46.7% (28/60), and mean PFS across all treatment lines of the palliative cohort was 10.2 months. Conclusions: We report retrospective single-center outcome data for the combined use of trastuzumab and pertuzumab in both early and metastatic Her2pos BCa in line with previously published data.

Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial

The Opti-HER HEART trial aimed to optimize activity while minimizing cardiac risk by combining trastuzumab, pertuzumab, and paclitaxel with non-pegylated liposomal doxorubicin in the treatment of HER2-positive early breast cancer. Patients with stage II–IIIB HER2-positive breast cancer received neoadjuvant trastuzumab, pertuzumab, paclitaxel, and a non-pegylated liposomal doxorubicin every three weeks for six cycles. The primary endpoint was cardiac safety during neoadjuvant therapy. Type A (symptomatic congestive heart failure) and B (asymptomatic reduction of left ventricular ejection fraction) cardiac events were evaluated. Secondary endpoints included the evaluation of the pathological complete response (pCR) rate and overall response rate, among others. As an ad-hoc exploratory analysis, the expression of 55 breast cancer-related genes, including the PAM50 genes, was measured in 58 baseline tumor samples and 60 surgical specimens. Eighty-three patients were recruited. The incidence of cardiac events during neoadjuvant treatment was 2.4%. No type A cardiac event was observed. The overall pCR rate was 56.6% (95% confidence interval (CI) 45.3–67.5%). The HER2-enriched subtype, which represented 52.0% of all baseline samples, was associated with a higher pCR rate compared to non-HER2-enriched tumors (83.3% vs. 46.3%; odds ratio 5.76, 95% CI 1.71–19.42). The association of subtype with pCR was independent of known clinicopathological variables, including hormone receptor status. Compared to baseline samples, surgical specimens showed a significant downregulation of proliferation-related genes (MKI67 and CCNB1) and ERBB2 levels, and a significant upregulation of luminal-related (ESR1 and PGR) and immune (CD8A) genes. The combination of dual HER2 blockade with trastuzumab and pertuzumab with paclitaxel and non-pegylated liposomal doxorubicin is associated with a low rate of cardiac events. The HER2-enriched subtype is associated with a high rate of pCR. clinicaltrials.gov, NCT01669239 , Registered 20 August 2012.

HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer.

Despite trastuzumab and pertuzumab improving outcome for patients with HER2-positive metastatic breast cancer, the disease remains fatal for the majority of patients. This study evaluated the anti-proliferative effects of adding anti-HER2 tyrosine kinase inhibitors (TKIs) to trastuzumab and pertuzumab in HER2-positive breast cancer cells. Afatinib was tested alone and in combination with trastuzumab in HER2-positive breast cancer cell lines. TKIs (lapatinib, neratinib, afatinib) combined with trastuzumab and/or pertuzumab were tested in 3 cell lines, with/without amphiregulin and heregulin-1β. Seven of 11 HER2-positive cell lines tested were sensitive to afatinib (IC50 < 80nM). Afatinib plus trastuzumab produced synergistic growth inhibition in eight cell lines. In trastuzumab-sensitive SKBR3 cells, the TKIs enhanced response to trastuzumab. Pertuzumab alone did not inhibit growth and did not enhance trastuzumab-induced growth inhibition or antibody-dependent cellular cytotoxicity. Pertuzumab enhanced response to trastuzumab when combined with lapatinib but not neratinib or afatinib. In two trastuzumab-resistant cell lines, the TKIs inhibited growth but adding trastuzumab and/or pertuzumab did not improve response compared to TKIs alone. Amphiregulin plus heregulin-1β stimulated proliferation of SKBR3 and MDA-MB-453 cells. In the presence of the growth factors, neither antibody inhibited growth and the TKIs showed significantly reduced activity. The triple combination of trastuzumab, pertuzumab and a TKI showed the strongest anti-proliferative activity in all three cell lines, in the presence of exogenous growth factors. In summary, addition of anti-HER2 TKIs to combined anti-HER2 monoclonal antibody therapy results in enhanced anticancer activity. These data contribute to the rationale for studying maximum HER2 blockade in the clinic.

Is there a role for adjuvant pertuzumab in HER2-positive breast cancer?

The outcomes of human epidermal growth factor receptor 2 (HER2)-positive breast cancer was dramatically changed by the introduction of targeted therapies against the HER2 receptor (1).The monoclonal antibody trastuzumab was the first HER2-directed treatment that demonstrated, together with chemotherapy, a significant improvement in treatment outcomes of this subgroup of patients, both in the metastatic (2) and neo-/adjuvant (3-7) settings, thus becoming the mainstay of treatment in HER2 positive breast cancer. The remarkable results achieved led to the development of additional HER2-targeted drugs, raising the hypothesis of a double-HER2 blockade against breast cancer.

Is there a role for adjuvant pertuzumab in HER2-positive breast cancer?

Is there a role for adjuvant pertuzumab in HER2-positive breast cancer?

Pertuzumab in HER2-positive breast cancer: a guide to its use

Pertuzumab (Perjeta®) is a humanized anti-HER2 monoclonal antibody that reduces the proliferation and survival of HER2-positive breast cancer cells by inhibiting dimerization of HER receptors on the cell surface, a key step in receptor-mediated mitogenic signalling. Pertuzumab binds to a different site on HER2 than trastuzumab and has a complementary action; the two agents act synergistically. Pertuzumab significantly increased progression-free survival, objective response rate and overall survival relative to placebo when each was given in combination with trastuzumab and docetaxel for the first-line treatment of HER2-positive metastatic/advanced breast cancer. Neoadjuvant therapy with pertuzumab in combination with trastuzumab and docetaxel increased breast pathological complete response rates to a significantly greater extent than trastuzumab and docetaxel alone and produced high 3-year survival rates. Pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel, and did not increase cardiac toxicity.

The use of combinations of monoclonal antibodies in clinical oncology.

Treatment with monoclonal antibodies is becoming increasingly important in clinical oncology. These antibodies specifically inhibit signaling pathways in tumor growth and/or induce immunological responses against tumor cells. By combining monoclonal antibodies several pathways may be targeted simultaneously, potentially leading to additive or synergistic effects. Theoretically, antibodies are very suitable for use in combination therapy, because of limited overlapping toxicity and lack of pharmacokinetic interactions. In this article an overview is given of preclinical and clinical data on twenty-five different combinations of antibodies in oncology. Some of these combinations have proven clinical benefit, for example the combination of trastuzumab and pertuzumab in HER2-positive breast cancer, which exemplifies an additive or synergistic effect on antitumor activity in clinical studies and the combination of nivolumab and ipilimumab, which results in significant increases in progression-free and overall survival in patients with advanced melanoma. However, other combinations may lead to unfavorable results, such as bevacizumab with cetuximab or panitumumab in advanced colorectal cancer. These combinations result in shorter progression-free survival and increased toxicity compared to therapy with a single antibody. In summary, the different published studies showed widely varying results, depending on the combination of antibodies, indication and patient population. More preclinical and clinical studies are necessary to unravel the mechanisms behind synergistic or antagonistic effects of combining monoclonal antibodies. Most research on combination therapies is still in an early stage, but it is expected that for several tumor types the use of combination therapy of antibodies will become standard of care in the near future.

Potentiation of trastuzumab emtansine (T-DM1)-driven antitumor activity by pertuzumab in a HER2-positive gastric cancer model.

e13502 Background: The efficacy and safety of T-DM1 combined with pertuzumab in HER2-positive breast cancer is currently being investigated in a phase III clinical trial (MARIANNE). Anti-HER2 therapy with T-DM1 combined with pertuzumab in HER2-positive gastric cancer is of great interest. In a previous study in a HER2-positive gastric cancer xenograft model, T-DM1 in combination with pertuzumab demonstrated enhanced antitumor activity compared with each agent alone, and potentiated ADCC and apoptosis activity (AACR, 2011). In this study, we investigated the mechanisms underlying the enhanced activity observed with these two drugs. Methods: The binding of T-DM1 to cell surface HER2 was measured in a HER2-positive human gastric cancer cell line (NCI-N87) by flow cytometry using Alexa Fluor 647-labeled T-DM1. The phosphorylation status of HER signaling molecules was assessed by Western blot, and cellular localization of T-DM1 was determined by fluorescence microscopy using labeled T-DM1 in the presence/absence of pertuzumab. Results: Binding of T-DM1 to cell surface HER2 was significantly increased in the presence of pertuzumab. Concomitant treatment with T-DM1 and pertuzumab led to a reduction of phosphorylated (p)EGFR or pHER3 in EGF or heregulin-stimulated cells, respectively, resulting in suppression of downstream pERK or pAkt pathways. Fluorescence microscopy revealed that pertuzumab facilitated the internalization of HER2-bound T-DM1 from the cell surface into the cytoplasm. Conclusions: Results suggest that the enhanced antitumor activity observed with the combination of T-DM1 and pertuzumab may be attributed to 1) increased binding of T-DM1 to HER2, which could potentially augment ADCC and diminish downstream HER2-signaling, and 2) increased T-DM1 internalization into the cytoplasm, which may potentiate tumor cell death caused by DM1. These results suggest that T-DM1 in combination with pertuzumab may provide clinical benefit for patients with HER2-positive gastric cancer.