Metastatic urothelial carcinoma harboring ERBB2/3 mutations dramatically respond

INTRODUCTION

Bladder cancer is considered to be one of the most aggressive neoplasms worldwide[1].For patients with distant metastases,the 5-year survival rate is as low as approximately 5%[2].Cisplatin based combination regimens have remained the standard first-line treatment for metastatic urothelial carcinoma(mUC)over the past decade.In the past,following the failure of first-line chemotherapy,paclitaxel,docetaxel,ifosfamide or gemcitabine monotherapy have been the most commonly used drugs,but are associated with low efficacy.

Several immune checkpoint inhibitors(ICIs)have been approved in recent years as first-line treatment for patients who ineligible to cisplatin or as second-line treatment for patients with mUC of the bladder.Despite the success of immune checkpoint blockades as a strategy for activating an antitumor immune response and promoting cancer regression,only a subset of patients experienced a durable clinical benefit.However,low objective response rates(13%-31%)have been observed in mUC[3-5].

The level of programmed death(PD)-1 expression and tumor mutation burden(TMB)are the two most commonly used predictive biomarkers but they are not sufficient[6-9].Therefore,there is an urgent need to identify biomarkers that can predict patient response or resistance to ICIs.Several clinical trials have attempted to identify robust biomarkers that can effectively predict the treatment response to ICIs in a subgroup analysis,including high levels of microsatellite instability(MSI-H),a mismatch repair deficiency(dMMR)[10],or tumor infiltrating cytotoxic T lymphocytes(TILs)[11,12].It is suggested thatmutations are associated with the efficacy of ICIs[13].

Here,we report a case of mUC harboringmutations,in which the level of PD-1 expression was negative and TMB was 3.4/Mb,demonstrating a durable response to anti-PD-1 antibodies in combination with chemotherapy as second-line therapy.

CASE PRESENTATION

Chief complaints

A 59-year-old man presented to our department complaining of bloody sputum for 2 wk on March 2020.He was diagnosed with urothelial cancer >13 years ago.

The patient refused CT-guided percutaneous lung biopsy.Since March 19,2020,the patient received six cycles of paclitaxel 300 mg plus sindilimab 200 mg once every 3 wk as second-line therapy and subsequently received sindilimab 200 mg once every 3 wk as maintenance treatment.

History of present illness

In May 2006,the patient presented with intermittent hematuria for 6 mo.On June 18,2006,he received transurethral resection of bladder tumor in local hospital,and the immunohistochemistry results revealed invasive urothelial cancer(grade 3).Due to repeated local recurrence,the patient received repeated(10 times)of transurethral resection of bladder tumor from June 2006 to July 2017.On July 5,2017,the patients received laparoscopic total cystectomy and ileal neobladder,the postoperative pathology showed high-grade papillary urothelial carcinoma(WHO grade III)with muscularis invasion(rpTNM,stage II).Pathology confirmed that the surgical margin was negative.In July 2018,the patient presented to local hospital for intermittent hematuria for 1 mo.The cystoscope showed neoplasm on urethra.The resection biopsy of the neoplasm confirmed high-grade papillary urothelial carcinoma(WHO grade III).The TNM stage was rTNM,stage IV.The patient received six cycles of GP(gemcitabine and cisplatin)as first-line chemotherapy from July 7,2018 to January 19,2019.On March 2020,the patient presented at our department complaining of bloody sputum for half a month.

History of past illness

In May 2006,the patient presented with intermittent hematuria for 6 mo.On June 18,2006,he received transurethral resection of bladder tumor in a local hospital,and immunohistochemistry revealed invasive UC(grade 3).Due to repeated local recurrence,the patient underwent repeated(10 times)transurethral resection of bladder tumor from June 2006 to July 2017.On July 5,2017,the patients received laparoscopic total cystectomy and ileal neobladder.Postoperative pathology showed highgrade papillary UC(WHO grade III)with muscularis invasion(rpTNM,stage II).Pathology confirmed that the surgical margin was negative.In July 2018,the patient presented to a local hospital because of intermittent hematuria for 1 mo.Cystoscopy showed urethral neoplasm.Resection biopsy of the neoplasm confirmed high-grade papillary UC(WHO grade III).The TNM stage was rTNM,stage IV.The patient received six cycles of gemcitabine and cisplatin(GP)as first-line chemotherapy from July 7,2018 to January 19,2019.In March 2020,the patient presented to our department complaining of bloody sputum for 2 wk.

Personal and family history

The patient’s previous medical history was hypertension,without a family history of cancer.

“Is it possible?” said the lord-in-waiting, “I never imagined it would be a little, plain, simple thing like that. She has certainly changed color at seeing so many grand people around her.”

Physical examination

The Eastern Cooperative Oncology Group score was 0 to 1,and the numeric pain intensity scale score was 0.There was an old surgical scar of about 11 cm in the lower abdomen.

No scolding from a teacher or preaching from a parent could linger as much as that hurt in my heart from the day a father’s eyes taught me kindness and strength and dignity. I never again joined the cruel herds16. I never again hurt someone for my own gain.

Laboratory examinations

Routine blood examination,blood biochemistry and urinalysis were normal.Serum tumor markers including -fetoprotein,carcinoembryonic antigen,cancer antigen(CA)125,CA 19-9,and ferritin were routinely monitored,and all were normal.

Informed written consent was obtained from the patient for publication of this report and any accompanying images.

Imaging examinations

Electrocardiography was normal.Chest computed tomography(CT)showed multiple lung metastases(Figure 1A).Enhanced abdominal CT showed postoperative changes of bladder cancer.Next-generation sequencing(NGS)showed PD-ligand 1(PD-L1)<1%,TMB 3.4/Mb,in-frame insertion of ERBB2[c.2313-2323dup ATACGTGATGGC(p.Y772-A775dup),21.6%]and ERBB3 amplification(2.5 times).

When the youth saw the King s daughter, he was so dazzled by her beauty, that he forgot all idea of danger, and went to the King to announce himself a suitor

FINAL DIAGNOSIS

As these two children would possibly inherit the kingdom, it was natural that their people should take a great interest in them, and it fell out that all the tranquil10 and peace-loving citizens desired that Placida should one day be their Queen, while the rash and quarrelsome hoped great things for Vivien

TREATMENT

Katrina Katrinka was like any other ordinary mother with two kids, a station wagon1（）, and a 60 foot tall crane in her back yard. The crane just showed up one morning. A construction company was building an apartment building down the street. One day the company went bankrupt2, and left their crane in Mrs. Katrinka s back yard. They just went bankrupt, and left her with a 60 foot tall crane in her back yard.

Horror gripped the heart of the World War I soldier as he saw his lifelong friend fall in battle. Caught in a trench1 with continuous gunfire whizzing over his head, the soldier asked his lieutenant2 if he might go out into the No Man s Land between the trenches3 to bring his fallen comrade back.

2 Now it happened one day that he had an audience with the King,3 and in order to appear a person of some importance4 he told him that he had a daughter who could spin straw into gold

OUTCOME AND FOLLOW-UP

After two cycles of treatment,chest CT revealed that the lung metastases were markedly reduced in size(Figure 1C and D).After six cycles,chest CT revealed further reduction of the lung metastases(Figure 1E and F).The patient received review irregularly in a local hospital or in our central hospital.At the time of the last follow-up on July 5,2021,the patient exhibited a durable partial response(Figure 1G and H)and progression-free survival(PFS)was 19 mo.No obvious side effects were observed and the patient was satisfied with the treatment.

DISCUSSION

ICIs have revolutionized the treatment of a range of solid tumors,including lung cancer,melanoma,esophageal cancer,and colorectal cancer with MSI-H for their durable clinical benefit and lower toxic effects[14,15].Since 2016,US Food and Drug Administration has approved five ICIs(atezolizumab,nivolumab,pembrolizumab,avelumab and durvalumab)the for the treatment of mUC(Table 1).Although ICIs are effective at treating metastatic urothelial bladder cancer,only a small proportion of patients receive a definite benefit.Currently,no single biomarker can clearly predict treatment response.To better predict the patients who are the mostly likely to benefit from ICIs,several ongoing trials have been conducted to identify effective biomarkers.With the wide application of NGS,an increasing number of new biomarkers are being discovered.

The epidermal growth factor receptor(EGFR)family of receptor tyrosine kinases consists of four members: EGFR1/ERBB1/HER1,ERBB2/HER2,ERBB3/HER3,and ERBB4/HER4(16).Signaling through these receptors regulates many key cellular activities,including cell division,migration,adhesion,differentiation and apoptosis[17].ERBB2/3 mutations(including point mutations and amplification)are observed in many types of solid tumors(breast cancer,gastric cancer,lung cancer and UC).An ERBB2 in-frame insertion into exon 20 has been associated with tyrosine kinase inhibitor resistance in lung adenocarcinoma[18].Moreover,ERBB3 overexpression has been associated with resistance to a large number of therapies in some cancers[19,20].ERBB2/3 mutations are associated with the treatment efficacy of PD-L1 monoclonal antibodies for gallbladder carcinoma[13].ICI monotherapy after the failure of first-line treatment is another reason for the low response rate associated with ICIs.

mUC(cTNM,stage IV).

Ongoing trials are investigating the regimens of ICIs combined with chemotherapy.The rationale is chemotherapy induces immunogenic cell death resulting in tumor antigens releasing and increasing MHC-I-mediated tumor antigen presentation which may enhance the effects of the immune response within the tumor.Another mechanism is directly modulating the activity and/or quantity of immunosuppressive cellular subsets[21,22].Several trials have explored the efficacy of ICIs in combination with chemotherapy for mUC.IMvigor-130 is a double blind,three-arm,multicenter,phase 3 trial investigating the use of atezolizumab as monotherapy or combined with platinum-based chemotherapy comparing with chemotherapy alone as first-line treatment for patients with locally advanced or metastatic bladder carcinoma[23].The addition of atezolizumab to platinum-based chemotherapy as a first-line treatment prolonged PFS in patients with mUC(mPFS 8.2 mo(95%CI: 6.5-8.3)in the atezolizumab plus platinum-based chemotherapy group and 6.3(6.2-7.0)mo in the placebo plus platinum-based chemotherapy group(stratified hazard ratio: 0.82,95%CI: 0.70–0.96;one-sided= 0.007).In addition,the median overall survival was 16.0(13.9–18.9)mo in the atezolizumab plus platinum-based chemotherapy group and 13.4(12.0–15.2)mo in the placebo plus platinum-based chemotherapy group(0.83,0.69–1.0;one-sided= 0.027).A similar three-arm,multicenter,phase 3 clinical trial(KEYNOTE-036)was established to investigate pembrolizumab as a monotherapy or combined with platinum-based chemotherapy against standard chemotherapy plus a placebo as firstline treatment.A phase 2 study also investigated cisplatin combined with gemcitabine plus ipilimumab compared with chemotherapy alone for patients with mUC.The objective response rate was as high as 69% and the completed response rate was 17%[2].

We first reported metastatic bladder UC harboring an ERBB2 in-frame insertion in an exon 20 mutation and ERBB3 amplification treated with paclitaxel plus sindilimab as second-line treatment.Although PD-L1 expression was negative and the TMB was low,the patient still achieved a durable response,with lung metastases being significantly reduced.At the last follow-up,the PFS was 19 mo.We will continue to focus on the follow-up treatment of this patient.However,we only included one case in this report,further studies and cases are required to confirm the relationship between ERBB2/3 mutations and response to ICIs in mUC.

CONCLUSION

This case indicates that mUC patients with ERBB2/3 mutations may benefit from ICIs.Further studies and cases are required to explore the ability of ERBB2/3 mutations to predict the efficacy of ICIs.

FOOTNOTES

Yan FF,Jiang Q,and Zhang XC were the patient’s oncologists,reviewed the literature,and contributed to manuscript drafting;Ru B and Fei XJ analyzed and interpreted the imaging findings;Ruan J and Zhang XC reviewed and edited the manuscript;Yan FF and Jiang Q contributed equally to this work;all authors read and approved the final manuscript.

the Zhejiang Medical Association,No.2018ZYC-A18.

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The authors declare that they have no conflict of interest.

The authors have read the CARE Checklist(2016),and the manuscript was prepared and revised according to the CARE Checklist(2016).

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China

Fei-Fei Yan 0000-0001-5003-096X;Qi Jiang 0000-0002-5307-3129;Bin Ru 0000-0003-0628-3243;Xiao-Jie Fei 0000-0002-8914-0573;Jian Ruan 0000-0003-1354-4720;Xiao-Chen Zhang 0000-0002-7014-868X.

Ma YJ

A

Ma YJ