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. 2023 Apr;9(2):a006262. doi: 10.1101/mcs.a006262

Complete response to chemoimmunotherapy with bevacizumab in synchronous multiple primary cancers: pulmonary adenocarcinoma and sarcomatoid carcinoma

Diogo Garcia 1,6, Isa Mambetsariev 1, Jeremy Fricke 1, Daniel Schmolze 2, Michelle Afkhami 2, Rifat Mannan 2, Pauline Kim 3, Shaira Therese Dingal 1, Bao Nguyen 4, Razmig Babikian 1, Yuman Fong 5, Ravi Salgia 1,✉
PMCID: PMC10240843  PMID: 37160318

Abstract

A small percentage of patients have multiple synchronous primary cancers at presentation. In the last five years, many regimens associated with immunotherapy and chemotherapy were approved for first-line metastatic non-small-cell lung cancer (NSCLC) and other solid tumors, but the study of immunotherapy when multiple cancers are present in one patient remains incomplete. Next-generation sequencing biomarkers and immunotherapy markers including PD-L1 can be effectively utilized in the diagnosis and treatment plan for multiple synchronous primary cancers. Immune biomarkers and PD-L1 expression warrant individualized treatments in synchronous primary adenocarcinoma and pulmonary sarcomatoid carcinoma. We describe the case of a patient with pulmonary sarcomatoid carcinoma and lung adenocarcinoma, metastatic to brain de novo. The patient achieved a complete response after only three cycles of carboplatin, paclitaxel, bevacizumab, and atezolizumab and remains free of any evidence of disease after 18 mo of maintenance therapy.

Keywords: lung adenocarcinoma, neoplasm of the lung

INTRODUCTION

For both men and women, lung cancer continues to be the leading cause of cancer-related deaths; reportedly up to 21% of lung cancer patients develop multiple synchronous primary cancers; and there has been an increase in the number of patients diagnosed with double primary cancers (Ferguson 1993; Noh et al. 2008; Lee et al. 2010; Weir et al. 2013). These rates of multiple primary cancers vary across tumor subtypes, age, exposure such as smoking history, and underlying germline factors and mutations (Travis et al. 2013). The reported increase in these rates is not yet completely defined, and factors such as improved diagnostic tests and more sophisticated treatment could be a potential cause (Coyte et al. 2014). However, occurrence of synchronous multiple primary cancers at presentation, with involvement in the lung, have been reported at higher rates, with one study showing 47% of lung patients diagnosed with multiple cancers (Kim et al. 2015b). Since the rapid adoption of next-generation sequencing of tumor tissue and circulating tumor DNA, it has become more common to study the genomic mutations associated with multiple primary cancers and understand the tumor heterogeneity associated with individual tumor subtypes (Whitworth et al. 2018; Mandelker and Ceyhan-Birsoy 2020). This advent has helped not only identify the individual tumor sites but also identify potential treatment options for these patients (Vogt et al. 2017).

In our case, we identify a patient who was diagnosed with lung adenocarcinoma and synchronous pulmonary sarcomatoid carcinoma found in the liver. Pulmonary sarcomatoid carcinomas (PSC) are a spectrum of histologically poorly differentiated carcinomas, accounting for <1% of all non-small-cell lung carcinoma (NSCLC) (Brambilla et al. 2001; Huang et al. 2013; Ung et al. 2016). PSC is well associated with a history of heavy smoking, chemotherapy resistance, and poor prognosis (Ishida et al. 1990; Yendamuri et al. 2012; Ouziane et al. 2014; Lin et al. 2016). The advent of tyrosine kinase inhibitors (TKIs) has shown that a certain subpopulation of PSC patients with molecular targets, including EGFR mutations, ALK fusions, and MET exon 14 skipping, responds well to TKIs, but the overall incidence rate of actionable mutations in PSC is relatively low (Schrock et al. 2017; Li et al. 2020; Yang et al. 2020). Concurrently, PSC tumors have a high incidence of KRAS mutations and PD-L1 expression, which makes them ideal candidates for immunotherapy (Vieira et al. 2016; Pecuchet et al. 2017). Clinical studies demonstrating the efficacy of immunotherapy on multiple primary cancers and PSC are limited, but one study of 37 patients with PSC showed an objective response rate (ORR) of 40.5% with a disease control rate of 64.8% regardless of PD-L1 expression (Deng et al. 2020; Domblides et al. 2020). Furthermore, there is preliminary evidence that immunotherapy efficacy may be high in patients with multiple lung cancer primaries (Asmar et al. 2017; Zhang et al. 2021). Therefore, we describe a case of a patient with dual synchronous primaries of pulmonary sarcomatoid carcinoma and lung adenocarcinoma, metastatic to the brain de novo. The patient achieved a complete response after only three cycles of carboplatin, paclitaxel, bevacizumab, and atezolizumab.

RESULTS

Clinical Presentation

The patient is a 78-yr-old male with Eastern Cooperative Oncology Group (ECOG) performance status 1, a former smoker, and a history of abdominal pain prior to diagnosis. A computed tomography (CT) scan demonstrated multiple liver lesions, retroperitoneal lymph nodes, and two right lung nodules. Subsequent positron emission tomography (PET) CT showed a right upper lobe spiculate nodule measuring 22 mm × 15 mm, a right lower lobe irregular nodule, measuring 14 mm × 8 mm, and multiple lesions in the liver with largest mass in the anterior right hepatic lobe measuring 71 mm × 49 mm (Fig. 1A). A brain magnetic resonance imaging (MRI) also revealed two enhancing right frontal lobe lesions measured at 12 and 2 mm (Fig. 2A). The patient underwent a core biopsy of the right lung which demonstrated poor differentiated adenocarcinoma consistent with lung primary (Table 1). The liver mass was also biopsied and showed poorly differentiated carcinoma with sarcomatoid features (Table 1). The lung and liver lesions demonstrated different morphologies and immunohistochemical profiles, and a site of origin could not be confidently assigned for the liver lesion.

Figure 1.

Figure 1.

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Positron emission tomography (PET) computed tomography (CT) of the whole body in coronal plane displaying the treatment response of the FDG-avid liver lesions. (A) At diagnosis. (B) After three cycles of therapy.

Figure 2.

Figure 2.

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Magnetic resonance imaging (MRI) of the brain scans in transverse, coronal, and sagittal planes displaying the treatment response in of the largest brain lesion. (A) At diagnosis. (B) 3 mo after treatment. (C) 9 mo after treatment.

Table 1.

Immunohistochemistry and molecular characterization

Pathology
 Diagnosis Poorly differentiated adenocarcinoma consistent with lung primary Poorly differentiated carcinoma with sarcomatoid features
 Specimen Site Right lung nodule Liver
 Immunostains  (+) AE1/AE3, CK7, Napsin A, TTF-1 CK-oscar, AE1/AE3 (weakly), CK7 (weakly), EMA (weakly), CK-8/18 (weakly), WT-1 (weakly), ERG, Fli-1 (weakly), actin (weakly), P53, Ki-67, vimentin
 Immunostains  (–) CK20 CK20, CK5/6, TTF-1, Napsin A, HepPar 1, S100, Mart 1, HMB-45, Calretinin, Factor VIII, CD31, CD34, MOC-31
Tumor markers (% AF)
 KRAS G12C (12%) G12V (15%)
 TP53 R306* (6%) I254S (6%), G154Afs*16 (8%)
 TERT c.-146C > T (9%)
 PD-L1  expression 95% 95%
 TMB Cannot be determined Cannot be determined
 MSI Stable Stable
 VUS RAD50 V683I (51%) RAD50 V683I (53%), ROS1 E2027K (9%)
Liquid biopsy (% cfDNA)
 KRAS G12V (1.2%)
 TP53 I254S (0.5%), G154fs (0.7%)
 TERT Promoter SNV (0.4%)
 TMB 16.43 mut/Mb
 MSI Stable
 VUS ROS1 E2027K (0.7%), PALB2 S270I (0.2%)
 SYN MSH6 G685G (0.7%), VHL P154P (0.3%), PDGFRA Y172Y (0.2%)
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(AF) Allelic fraction, (cfDNA) circulating-free DNA, (MSI) microsatellite instability, (PD-L1) programmed death ligand-1, (SYN) synonymous alteration, (TMB) tumor mutational burden, (VUS) variants of unknown significance, (SNV) single-nucleotide variant.

Molecular testing was performed to understand tumor origin. Guardant360 liquid biopsy resulted in KRAS G12V mutation, TP53 I254S mutation, TP53 G154fs mutation, and a tumor mutational burden (TMB) at 16.43 mut/Mb along with other mutations (Table 2). Solid tumor tissue panel HopeSeq Lung was performed on the pulmonary nodule and showed KRAS G12C mutation at an allele frequency of 12%, TP53 R306* mutation at an allele frequency of 6% and PD-L1 (22C3) tumor proportion score (TPS) of 95%. The same tissue panel was performed on the liver biopsy and showed KRAS G12V mutation at an allele frequency of 15%, TP53 I254S mutation at an allele frequency of 6%, TP53 G154Afs*16 mutation at an allele frequency of 8% and PD-L1 (22C3) TPS of 95% along with other alterations (Table 1). Because both samples and the liquid biopsy had the same driver mutations (KRAS and TP53), the diagnosis of synchronous primary pulmonary sarcomatoid carcinoma, variant pleomorphic, alongside lung adenocarcinoma, metastatic to the liver, retroperitoneal lymph nodes, and brain was made with the staging of IVB (T1cNxM1c).

Table 2.

Variant table

Gene Chromosome HGVS DNA reference HGVS protein reference Variant type Predicted effect dbSNP/dbVar ID Genotype
KRAS (c.34G > T, p.G12C) 12p12.1 NM_004985.5:c.34G > T NP_004976.2:p.Gly12Cys Missense Gain, pathogenic dbSNP: rs121913530 Heterozygous
TP53 (c.916C > T, p.R306*) 17p13.1 NM_000546.6:c.916C > T NP_000537.3:p.Arg306Ter Nonsense Loss, pathogenic dbSNP: rs121913344 Heterozygous
RAD50 (c.2047G > A, p.V683I) 5q31.1 NM_005732.4:c.2047G > A NP_005723.2:p.Val683Ile Missense Loss, VUS dbSNP: rs367925756 Heterozygous
KRAS (c.35G > T, p.G12V) 12p12.1 NM_004985.5:c.35G > T NP_004976.2:p.Gly12Val Missense Gain, pathogenic dbSNP: rs121913529 Heterozygous
TP53 (c.761T > G, p.I254S) 17p13.1 NM_000546.6:c.761T > G NP_000537.3:p.Ile254Ser Missense Gain, pathogenic dbSNP: rs1330865474 Heterozygous
TP53 (c.461del, p.G154Afs*16) 17p13.1 NM_000546.6:c.460_463del NP_000537.3:p.Gly154fs Frameshift, deletion Loss, pathogenic dbSNP: rs1567553658 Heterozygous
TERT (c.-146C > T, p.C250T) 5p15.33 NM_198253.3 p.C250T Missense Loss, pathogenic N/A Heterozygous
RAD50 (c.2047G > A, p.V683I) 5q31.1 NM_005732.4:c.2047G > A NP_005723.2:p.Val683Ile Missense Loss, VUS dbSNP: rs367925756 Heterozygous
ROS1 (c.6079G > A, p.E2027K) 6q22.1 NM_001378902.1 p.E2027K Missense Loss, VUS dbSNP2/6/2023rs1484038087 Heterozygous
TP53 (c.460_463del, p.Gly154fs) 17p13.1 NM_000546.6:c.460_463del NP_000537.3:p.Gly154fs Frameshift, deletion Loss, pathogenic dbSNP: rs1567553658 Heterozygous
PALB2 (c.809G > T, p.S270I) 16p12.2 NM_024675.4 p.S270I Missense Loss, VUS N/A Heterozygous
MSH6 (c.2055T > C, p.G685G) 2p16.3 NM_000179.3:c.2055T > C NP_000170.1:p.Gly685= Missense, synonymous Loss, VUS dbSNP: rs760299985 Heterozygous
VHL (c.462A > G, p.P154P) 3p25.3 NM_000551.4:c.462A > G NP_000542.1:p.Pro154= Missense, synonymous Gain, VUS dbSNP: rs1060503562 Heterozygous
PDGFRA (c.516C > T, p.Y172Y) 4q12 NM_006206.6:c.516C > T NP_006197.1:p.Tyr172= Missense, synonymous Loss, VUS dbSNP: rs1046079554 Heterozygous
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(VUS) Variant of unknown significance, (N/A) not available.

Based on the molecular testing results and the pathological diagnosis confirmation, the patient was started on carboplatin AUC5, paclitaxel 175 mg/m2, bevacizumab 15 mg/kg, and atezolizumab 1200 mg/dose (ABCP) every 3 wk. The two brain lesions were treated with stereotactic radiosurgery (SRS) at a dose of 20 Gray in one fraction. After three cycles, with a dose reduction due to neuropathy after the first cycle to carboplatin AUC 4 and paclitaxel 150 mg/m2, follow-up scans showed both morphologic and metabolic partial response of all lesions, including in the central nervous system (CVS) (Figs. 1B, 2B,C). With the patient's consent and wishes, a robotically assisted liver resection was performed, and the patient recovered brilliantly and was discharged the following day. A pathology report showed extensive hyalinization, necrosis, and an old hemorrhage, which were all suggestive of treatment effect. The patient achieved a complete response after only 15 wk upon initiation of systemic therapy. Eighteen months later, he continues maintenance monotherapy with atezolizumab 1200 mg every 3 wk and has no evidence of disease.

DISCUSSION

Multiple primary tumors involve one or more tumors in an individual at the same time after it has been ruled out that one of the lesions is a metastasis of others (Vogt et al. 2017). In lung cancer, it has been reported that incidence of multiple primaries varies from 13.4% to 22% with high variability based on study populations (Rosso et al. 2009; Sánchez de Cos Escuín et al. 2016). For many of these patients the secondary cancer type is usually of lung origin, most commonly SCLC, but 19% are reported to be of unspecified origin (Bhaskarla et al. 2010). Pulmonary sarcomatoid carcinomas are extremely rare, accounting for <1% of all NSCLC (Yendamuri et al. 2012). The diagnosis of PSC is mainly based on morphological features, and although immunohistochemical stains can be helpful, molecular testing may be necessary to determine primary site origin (Terra et al. 2016; Huey et al. 2019). PSC often are diagnosed with distant metastases in unusual sites such as pancreas, kidneys, and the digestive tract, which results in a poor prognosis and PSC has historically been shown to be chemoresistant, where up to two-thirds of patients progress on first evaluation (Giroux Leprieur et al. 2013; Vieira et al. 2013). Although not usually seen in NSCLC, metastasis resections have been reported with satisfactory results and were offered based on patient desires (Gomez et al. 2016). However, with the advent of immunotherapy and targeted therapy, deep and long-lasting responses have been seen (Velcheti et al. 2013; Fallet et al. 2015; Schrock et al. 2017; Domblides et al. 2020). Our patient had all the commonly established pathological, radiological, and clinical features of primary sarcomatoid carcinoma and underwent a liver resection during systemic chemotherapy and immunotherapy.

Because of the low incidence of PSC and the relatively new adoption of a comprehensive genomic sequencing to clinical practice, the molecular profile of PSC is widely variable and needs to be refined (Terra et al. 2016; Li et al. 2017; Schrock et al. 2017; Zhou et al. 2021). TP53 mutation frequency in PSC is reported ranging from 22% to 73% and KRAS mutations are the second most common in PSC, reports range from 15% to 39%, and frequently cooccur with TP53 mutations (Schrock et al. 2017; Jiao et al. 2018; Mehrad et al. 2018). Notably, recent findings suggest that PSCs may develop through further undifferentiation of the adenocarcinoma or common tumor cell progenitor through nongenetic mechanisms such as epithelial-to-mesenchymal transition (Pelosi et al. 2003, 2010; Manzotti et al. 2019).

Another characteristic of PSC is its immunogenicity, and elevated TMB detected in patients suggests a high amount of tumoral neoantigens, which should induce strong tumor immunogenicity and predict response to immunotherapy (Kowanetz et al. 2016; Reck et al. 2016; Schrock et al. 2017). TMB recently received FDA approval as a predictive biomarker for pembrolizumab in all solid tumors with a TMB ≥10 mutations/Mb based on results of KEYNOTE-158 (Marabelle et al. 2020). Furthermore, a recent Phase IIa multibasket study of atezolizumab in advanced solid tumors showed efficacy of TMB as a predictive biomarker of response with TMB ≥16 mutations/Mb (Friedman et al. 2022). Marie Wislez et al. had published a series of 37 consecutive PSC cases that received immunotherapy in the second and third line and the ORR was 40.5% independent of PD-L1 status, which is larger than historical 8%–16% with chemotherapy in the first-line (Vieira et al. 2016; Maneenil et al. 2018; Domblides et al. 2020). PD-L1 positivity varies widely in PSC cases, from 53%–94%, which may be justified by different methods and cohorts (Velcheti et al. 2013; Kim et al. 2015a; Vieira et al. 2016; Domblides et al. 2020). Even with this heterogeneity, PD-L1 positivity in PSC is routinely higher than the historical 20%–60% in usual NSCLC histologies (Velcheti et al. 2013; Kim et al. 2015a; Yu et al. 2016). Notably, our patient was PD-L1 positive with a score of 95% and achieved a complete response with only three cycles of therapy.

In the past few years, several regimens were approved for first line metastatic NSCLC and other cancer types, which complicates the treatment options for patients with multiple cancers (Antonia et al. 2017; Wolchok et al. 2017; Larkin et al. 2019). The choice of a regimen that includes bevacizumab was based on the poorly differentiated histology and the prognosis of pulmonary sarcomatoid carcinoma. As the patient had pulmonary sarcomatoid carcinoma detected in the liver, it was also supported by the results of the IMpower 150 trial, in which the subgroup with previous liver metastasis had a median overall survival gain of four months, with ABCP (Socinski et al. 2021). The efficacy of immunotherapy in patients with multiple primary cancers is limited but one case series of patients with multiple primary malignancies with advanced melanoma showed that six out of 11 patients had complete response to immunotherapy (Ebia et al. 2021).

In conclusion, this case report confirms the efficacy of immunotherapy in patients with dual synchronous primary tumors and to the best of our knowledge this is the first reported complete response in a patient with both lung adenocarcinoma and pulmonary sarcomatoid carcinoma after treatment. Our report also shows the importance of molecular testing in tumors with differential pathological immunostains to determine the best course of therapy and we advocate that more clinical studies are required that evaluate the efficacy of immunotherapy in patients with multiple primary cancers.

METHODS

The patient's tumor tissue was analyzed with City of Hope's in-house insurance-reimbursable CLIA-certified targeted panel HopeSeq, a broad-based mutation sequencing panel that evaluates full exon of 523 genes, copy-number variations, microsatellite instability, tumor mutation burden, PD-L1 IHC, and a fusion analysis panel of more than 5000 selected rearrangements in 165 genes. The patient's liquid biopsy was analyzed through Guardant360, a commercial targeted next-generation sequencing service available as an insurance-reimbursable CLIA assay.

ADDITIONAL INFORMATION

Data Deposition and Access

All data presented in the case report was included in the manuscript, and raw sequencing data could not be uploaded as it was sequenced through insurance-reimbursable CLIA-certified commercial panels and consent to upload was not obtained. The variants were submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers SCV003804197, SCV003804198, and SCV003804201–SCV003804209.

Ethics Statement

The City of Hope Institutional Review Board approved this study and informed consent was obtained under IRB# 07047.

Acknowledgments

The authors thank City of Hope nurses and supportive staff for their dedication to their patients.

Author Contributions

All authors participated in the conceptualization, methodology, data curation, original draft preparation, and reviewing and editing the final manuscript. R.S. provided supervision and funding.

Funding

The work was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572.

Competing Interest Statement

The authors have declared no competing interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data presented in the case report was included in the manuscript, and raw sequencing data could not be uploaded as it was sequenced through insurance-reimbursable CLIA-certified commercial panels and consent to upload was not obtained. The variants were submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers SCV003804197, SCV003804198, and SCV003804201–SCV003804209.

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