Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3)

Seo, Seyoung; Ryu, Min Hee; Park, Young Soo; Ahn, Ji Yong; Park, Yangsoon; Park, Sook Ryun; Ryoo, Baek Yeol; Lee, Gin Hyug; Jung, Hwoon Young; Kang, Yoon Koo

doi:10.1007/s10120-018-0891-1

Cited by 101 publications

(72 citation statements)

References 32 publications

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“…Although HER2-targeted therapy has been commonly used in second-line treatment of HER2-positive breast cancer (26), it has failed to be established as second-line treatment in gastric cancer. Consistent with previous studies in gastric cancer (11)(12)(13), we found that two out of three patients with HER2-positive disease treated with trastuzumab in combination with chemotherapy were converted to HER2negative. In addition, our data suggest that cytotoxic chemotherapy can also lead to loss of HER2-positive tumor cells.…”

Section: Discussionsupporting

confidence: 92%

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Changes in HER2 Expression and Amplification Status Following Preoperative Chemotherapy for Gastric Cancer

Shu

Iimori

Nakanishi

et al. 2018

In Vivo

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Background: It is essential to establish a strategy for second-line treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer; however, HER2 expression status after chemotherapy treatment is not routinely determined. Materials and Methods: We analyzed 25 cases of gastric cancer that received preoperative chemotherapy and selected the six pre-treatment samples that were HER2positive. Pre-and post-treatment tumor samples were examined for HER2 expression, and for HER2, epidermal growth factor receptor (EGFR), and hepatocyte growth factor receptor (MET) gene amplification. Results: Three patients had been treated with trastuzumab plus chemotherapy, and three patients with cytotoxic chemotherapy alone. Only one case that had an initial HER2 score of 3+ and had received trastuzumab plus chemotherapy remained HER2-positive after treatment. Decrease or loss of HER2 expression and amplification was observed in the other five patients. Amplification of EGFR or MET was not observed in any preor post-treatment specimens. Conclusion: Our data suggest that trastuzumab plus chemotherapy or chemotherapy alone may induce loss of HER2 positivity.

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Section: Discussionsupporting

confidence: 92%

“…One explanation is that HER2 positivity is lost after HER2-targeted treatment. In breast and gastric cancer, it has been reported that previously treated tumors may lose HER2 expression after HER2-targeted therapy (9)(10)(11)(12)(13). The selective pressure of HER2-targeted treatment has been proposed as one of the mechanisms whereby HER2 expression is lost.…”

mentioning

confidence: 99%

Changes in HER2 Expression and Amplification Status Following Preoperative Chemotherapy for Gastric Cancer

Shu

Iimori

Nakanishi

et al. 2018

In Vivo

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“…This could mean HER2 receptor density is lower in GC than BC even in homogenously stained tumors; comparison of HER2 mRNA levels between GC and BC tumors with homogenous HER2 staining does not support this hypothesis (Roche, Data on file); however, more accurate methods to measure exact HER2 receptor density per cell may be needed to test this assumption. Discordance in HER2 expression between primary and metastatic GC has been reported previously, suggesting that HER2 status can be altered or lost during disease progression [36,37]; HER2 status was confirmed using a primary tumor sample for approximately 90% of patients in GATSBY (all had status confirmed using tissue collected prior to first-line therapy). HER2 expression could also have changed before versus after first-line HER2-targeted therapy [38], and in primary versus metastatic tumors during disease progression.…”

Section: Discussionmentioning

confidence: 65%

Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2-positive advanced gastric/gastroesophageal junction cancer

et al. 2019

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Background Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology. Methods Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included. Results Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68-1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94-2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup. Conclusions Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy. Clinical trials registration NCT01641939 (https ://clini caltr ials.gov/ct2/show/NCT01 64193 9).

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“…Studies that evaluated changes in HER2 protein expression in AGC patients receiving trastuzumab-containing regimens by comparison of matched pre-and post-treatment samples have demonstrated a loss of HER2 [33,34]. In the aforementioned T-ACT study [21], given that collection of new tumor biopsy samples at the time of study enrollment (after progression on prior trastuzumab therapy) was not mandatory, reassessment of HER2 positivity was performed for only 16 out of 44 patients.…”

Section: Loss Of Her2 Protein Expressionmentioning

confidence: 99%

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Mitani

Kawakami

2020

Cancers

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Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies. basis of these results, trastuzumab was approved for AGC with a high HER2 expression level, and trastuzumab-containing regimens are now a standard option for the first-line treatment of such patients, who accounted for 7% to 17% of all individuals with gastric cancer [3-5]. Derivatives of the ToGA Regimen in the First-Line SettingThe ToGA trial adopted a regimen of cisplatin combined with either 5-fluorouracil (5-FU) or capecitabine, whereas subsequent prospective studies found similar treatment outcomes with regimens containing oxaliplatin or tegafur-gimeracil-oteracil (S-1). In a single-arm, nonrandomized phase II trial (HER2-based strategy in stomach cancer (HERBIS)-1) performed in Japan [6], trastuzumab in combination with S-1 plus cisplatin yielded a confirmed ORR of 68%, with a median OS and a median PFS of 16.0 and 7.8 months, respectively, in HER2-positive AGC patients with measurable lesions, with these results being similar to those of the ToGA trial [2]. Similar efficacy was also apparent in AGC patients without measurable lesions (HERBIS-1B study) [7]. Three phase II studies that assessed the combination of trastuzumab with capecitabine plus oxaliplatin reported a median OS, a median PFS, and an ORR of 13.8 to 21.0 months, 7.1 to 9.8 months, and 46.7% to 67.3%, respectively [8][9][10]. Trastuzumab in combination with S-1 plus oxaliplatin was also shown to provide a similar treatment outcome in a phase II study, with a median OS, a median PFS, and an ORR of 18.1 months, 8.8 months, and 70.7%, respectively [11]. A meta-analysis of data from these trials revealed that S-1 or oxaliplatin can substitute effectively for capecitabine or 5-FU or for cisplatin, respectively [12].Immune checkpoint inhibitors such as antibodies to programmed cell death-1 (PD-1) have recently revolutionized treatment strategies for advanced cancer. Given that trastuzumab was found to stimulate T cell responses [13], the combination of trastuzumab-containing regimens with antibodies to PD-1 is receiving attention. A phase II study including 37 patients with HER2-positive AGC treated in the first-line setting with capecitabine, oxaliplatin, and trastuzumab in combination with the anti-PD-1 antibody pembrolizumab reported an ORR of 83%, with a median PFS of 11.4 months and a median ...

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Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3)

Cited by 101 publications

References 32 publications

Changes in HER2 Expression and Amplification Status Following Preoperative Chemotherapy for Gastric Cancer

Changes in HER2 Expression and Amplification Status Following Preoperative Chemotherapy for Gastric Cancer

Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2-positive advanced gastric/gastroesophageal junction cancer

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

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