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Clinicopathologic Features of NSCLC Diagnosed During Pregnancy or the Peripartum Period in the Era of Molecular Genotyping

Open ArchivePublished:June 10, 2016DOI:https://doi.org/10.1016/j.jtho.2016.05.031

      Abstract

      Introduction

      Cancer will be diagnosed in one in 1000 women during pregnancy. The outcomes of NSCLC diagnosed during pregnancy are dismal, with most patients dying within 1 year. Actionable mutations are more likely to be found among younger patients with NSCLC. However, most previous reports of NSCLC diagnosed during pregnancy did not include molecular genotyping.

      Methods

      We performed a retrospective analysis of patients seen at our institution between 2009 and 2015 to identify women in whom NSCLC was diagnosed during pregnancy or the peripartum period and determined clinicopathologic features, including molecular genotype.

      Results

      We identified 2422 women with NSCLC, including 160 women of reproductive age. Among the women of reproductive age, eight cases of NSCLC diagnosed during pregnancy or the peripartum period were identified; all were diagnosed in minimal or never-smokers with metastatic adenocarcinoma. Six of these patients were found to have anaplastic lymphoma kinase gene (ALK) rearrangements, whereas the remaining two were EGFR mutation positive. We observed a borderline significant association between a diagnosis of NSCLC during pregnancy or the peripartum period and ALK positivity (p = 0.053). All eight women in whom NSCLC was diagnosed during pregnancy or the peripartum period received treatment with genotype-directed therapies after delivery. The median overall survival has not been reached at a median follow-up of 30 months.

      Conclusions

      Although a diagnosis of NSCLC during pregnancy or the peripartum period is rare, diagnostic evaluation should not be delayed in pregnant women presenting with symptoms worrisome for lung cancer. Evaluation should include testing for targetable molecular alterations.

      Keywords

      Introduction

      With an estimated incidence of 1 in 1000, a diagnosis of cancer during pregnancy is a rare occurrence.
      • Peccatori F.A.
      • Azim Jr., H.A.
      • Orecchia R.
      • et al.
      Cancer, pregnancy, and fertility: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up.
      Pregnant patients tend to present at an advanced stage, largely owing to diagnostic delays fueled by attribution of symptoms to other diseases and efforts to ensure fetal well-being.
      • Boussios S.
      • Han S.N.
      • Fruscio R.
      • et al.
      Lung cancer in pregnancy: report of nine cases from an international collaborative study.
      Even when a diagnosis is made early, management strategies must account for the potential increased risk for complications during the period of fetal organogenesis.
      National Toxicology Program
      NTP monograph: developmental effects and pregnancy outcomes associated with cancer chemotherapy use during pregnancy.
      As cultural shifts have fostered a trend toward childbearing closer to the end of reproductive age, an increase in the incidence of cancer diagnosed during pregnancy is anticipated. To date, there have been more than 50 published cases of lung cancer during pregnancy. The patients, most of whom were smokers,
      • Azim H.A.
      • Peccatori F.A.
      • Pavlidis N.
      Lung cancer in the pregnant woman: to treat or not to treat, that is the question.
      • Pavlidis N.
      Lung cancer during pregnancy: an emerging issue.
      presented at a median age of 36 years and median gestation of 29 weeks.
      • Azim H.A.
      • Peccatori F.A.
      • Pavlidis N.
      Lung cancer in the pregnant woman: to treat or not to treat, that is the question.
      The median survival for patients in whom lung cancer was diagnosed during pregnancy in these reports was quite dismal, with most patients dying within 1 year.
      • Azim H.A.
      • Peccatori F.A.
      • Pavlidis N.
      Lung cancer in the pregnant woman: to treat or not to treat, that is the question.
      • Pavlidis N.
      Lung cancer during pregnancy: an emerging issue.
      In the past decade, it has become increasingly apparent that NSCLC comprises distinct molecular subgroups with characteristic clinicopathologic features. However, most published cases describing lung cancer in pregnancy predate the adoption of routine molecular profiling.
      • Boussios S.
      • Han S.N.
      • Fruscio R.
      • et al.
      Lung cancer in pregnancy: report of nine cases from an international collaborative study.
      • Janne P.A.
      • Rodriguez-Thompson D.
      • Metcalf D.R.
      • et al.
      Chemotherapy for a patient with advanced non-small-cell lung cancer during pregnancy: a case report and a review of chemotherapy treatment during pregnancy.
      Given that younger age is associated with increased likelihood of harboring actionable molecular alterations and that treatment with targeted therapies is associated with superior outcomes than with standard chemotherapy, it is possible that the previously reported poor outcomes may not be applicable in the modern era.
      • Kris M.G.
      • Johnson B.E.
      • Berry L.D.
      • et al.
      Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
      • Shaw A.T.
      • Yeap B.Y.
      • Solomon B.J.
      • et al.
      Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.
      • Sacher A.G.
      • Dahlberg S.E.
      • Heng J.
      • et al.
      Association between younger age and targetable genomic alterations and prognosis in non-small-cell lung cancer.
      To investigate the frequency of lung cancer diagnoses during pregnancy or the peripartum period among genetically defined subsets of NSCLC, we performed a retrospective analysis of consecutive patients seen at our institution between 2009 and 2015. We present a series of eight women in whom NSCLC was diagnosed during pregnancy or the peripartum period.

      Methods

      We performed a retrospective review of records of consecutive patients with NSCLC seen at Massachusetts General Hospital from 2009 to 2015 to identify patients in whom NSCLC was diagnosed during pregnancy or the peripartum period. The peripartum period was defined as the time from the last month of pregnancy until 12 weeks after delivery. Clinical information was obtained from several databases that contained information for 2422 women with NSCLC and confirmed by review of the electronic medical record. The study was approved by the institutional review board at Massachusetts General Hospital. Descriptive statistics were used to compare baseline characteristics. Fisher's exact test was used for two sample comparisons. Statistical significance was defined as a p value less than 0.05.

      Results

      Patients

      From the 2422 women with NSCLC, we identified 160 women of reproductive age, defined as 18 to 45 years old. In eight (5%) of these 160 women, NSCLC was diagnosed during pregnancy or the peripartum period (Fig. 1). All eight patients presented with metastatic lung adenocarcinoma and had either minimal or no prior tobacco exposure (Table 1). The median age at diagnosis was 35 years (range 29–43 years). The lung cancer diagnoses were made in all trimesters. The predominant symptoms at presentation during pregnancy or the peripartum period (see Table 1) were similar to those routinely observed in patients with lung cancer and included cough and dyspnea (cases 1, 5, and 7), fatigue (case 5), weight loss (case 6), and pain at sites of metastatic involvement (cases 6 and 8). Two women whose cancer was diagnosed in their first trimester presented with symptoms attributable to brain metastasis, including extremity weakness (case 3) and seizure (case 4).
      Figure thumbnail gr1
      Figure 1Incidence of pregnancy/peripartum NSCLC at a single institution between 2009 and 2015. ALK, anaplastic lymphoma receptor tyrosine kinase.
      Table 1Characteristics of Eight Patients with Diagnosis of NSCLC during Pregnancy or the Peripartum Period
      CaseAge at Diagnosis (y)RaceSmoking HistoryGestational Age at DiagnosisTumor Histologic TypeStage at Diagnosis (TNM, Seventh Edition)Molecular

      Driver
      136WhiteNever30 wkAdenocarcinomaIVaALK
      236WhiteFormer, 4 pack-years12 wk postpartumAdenocarcinomaIVbALK
      333WhiteNever5 wkAdenocarcinomaIVbALK
      429WhiteNever9 wkAdenocarcinomaIVbALK
      535WhiteNever15 wkAdenocarcinomaIVbALK
      631WhiteFormer, 14 pack-years38 wkAdenocarcinomaIVbALK
      743AsianNever2 wk postpartumAdenocarcinomaIVaEGFR exon 19 deletion
      835AsianNever8 wk postpartumAdenocarcinomaIVbEGFR exon 19 deletion
      TNM, tumor, node, and metastasis classification; ALK, anaplastic lymphoma kinase gene.

      Correlation between Molecular Features and NSCLC Diagnosis during Pregnancy or the Peripartum Period

      Of the women of childbearing age, NSCLC harboring EGFR, anaplastic lymphoma kinase gene (ALK), KRAS, or ROS1 alterations was diagnosed in 126 (79%) women (see Fig. 1). Among these 126 women, 48 (38%) had EGFR-mutant NSCLC and 48 (38%) had ALK-positive NSCLC. ROS1-positive or KRAS-mutant NSCLC was diagnosed in 11 (9%) and 19 (15%) women of childbearing age, respectively. Consistent with previous reports, a greater proportion of all women with ALK-positive (31%) and ROS1-positive (38%) NSCLC were of childbearing age than in the EGFR-mutant (9%) and KRAS-mutant (6%) groups (Table 2).
      • Shaw A.T.
      • Yeap B.Y.
      • Mino-Kenudson M.
      • et al.
      Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
      • Bergethon K.
      • Shaw A.T.
      • Ou S.H.
      • et al.
      ROS1 rearrangements define a unique molecular class of lung cancers.
      Table 2Correlation between Driver Mutation Status and Diagnosis of NSCLC during Pregnancy or the Peripartum Period
      Oncogenic DriverTotal No. Women (n = 2422)No. Women of Childbearing Age (Age 18–45 y) (n = 160)Total No. Pregnant Patients (% Relative to Total No. Women of Childbearing Age by Driver) (n = 8)
      ALK156486 (12.5%)
      EGFR547482 (4%)
      KRAS311190
      ROS129110
      Unknown/other1379340
      ALK, anaplastic lymphoma kinase gene.
      NSCLC was diagnosed during pregnancy or peripartum in 12.5% (six of 48) of the ALK-positive patients, 4% (two of 48) of the EGFR-mutant patients, 0% (none of 11) of the ROS1-positive patients, and 0% (none of 19) of the KRAS-mutant patients of childbearing age with a diagnosis of NSCLC. In all cases of ALK-positive NSCLC, the diagnosis was made using the U.S. Food and Drug Agency–approved Vysis Break-Apart Dual-Color Fluorescence In Situ Hybridization Probe Kit (Abbott Molecular, Des Plaines, IL). For cases 7 and 8, the diagnosis of NSCLC harboring an EGFR exon 19 deletion was made by next-generation sequencing. Testing for additional oncogenic drivers was performed for all eight cases, and no concurrent oncogenic mutations were detected. The small number of women of reproductive age limited drawing statistical conclusions about predisposition toward presentation during pregnancy or the peripartum period by mutation status. However, when women of reproductive age with ALK-positive NSCLC were compared with women of reproductive age with ALK-negative NSCLC, there was an association between NSCLC diagnosis during pregnancy or the peripartum period and ALK positivity of borderline statistical significance (p = 0.0533).

      Pregnancy Outcomes

      Two patients, both of whom had their cancer diagnosed early in gestation, elected for pregnancy termination. The remaining six continued their pregnancy after the diagnosis of NSCLC or had their disease diagnosed after delivery. In the two of these six patients, complications developed during pregnancy. Patient 8 had a preexisting history of cervical insufficiency diagnosed during prior pregnancies. She underwent urgent cesarean section at 25 weeks in the setting of cervical incompetence. Her child died 3 weeks after delivery. Placental abruption prompting an emergency cesarean section at 29 weeks developed in patient 6. Although her child suffered from intrauterine growth restriction, the baby is currently doing well. The remaining patients delivered healthy babies.

      Treatment Outcomes

      None of the women were treated with targeted therapies during pregnancy. However, patient 4 received carboplatin and paclitaxel during her second and third trimesters. Patient 4 was also treated with a gamma knife for symptomatic brain metastases during her second trimester. Overall, the median time to initiation of systemic therapy after diagnosis was 4 weeks (range 1–8 weeks). All of the women received treatment with genotype-directed therapies after delivery, with most receiving targeted agents in the first-line setting.
      For the six ALK-positive patients who received crizotinib, progression-free survival (PFS) ranged from 5 weeks to 60 weeks, with a median of 16 weeks. Of the four women with PFS less than or equal to 16 weeks while receiving crizotinib, one progressed in the lungs only (patient 5) and the others had both extracranial and intracranial progression (patients 3, 4, 6). For the two patients with EGFR-mutant NSCLC, PFS was 28 weeks and 18 weeks. Seven of the eight patients went on to receive additional tyrosine kinase inhibitors (TKIs) after development of acquired resistance to their first targeted agent. The median overall survival in the eight cases has not been reached at a median follow-up of 30 months after diagnosis. All of the women are alive with the exception of patient 2 who died of leptomeningeal spread of her NSCLC. Notably, all the patients survived beyond 4.5 months after diagnosis, which is the median overall survival previously reported in the literature for women diagnosed with NSCLC during pregnancy (Table 3).
      • Pavlidis N.
      Lung cancer during pregnancy: an emerging issue.
      Table 3Clinical Summaries of the Cases of Eight Patients with a Diagnosis of NSCLC during Pregnancy or the Peripartum Period
      Case12345678
      Pregnancy outcomes
      Gestational age at diagnosis30 wk12 wk postpartum5 wk9 wk15 wk28 wk2 wk postpartum8 wk postpartum
      Timing of delivery32 wkN/APregnancy termination34 wkPregnancy termination29 wkN/AN/A
      Pregnancy complicationsNoneNone___None___Placental abruptionNonePremature delivery at 25 wk due to cervical incompetence
      Treatment outcomes
      Interval from diagnosis to first systemic therapy4 wk4 wk4 wk8 wk1 wk2 wk4 wk6 wk
      First TKI (line of therapy)Crizotinib (3)Crizotinib (2)Crizotinib (1)Crizotinib (2)Crizotinib (1)Crizotinib (1)Gefitinib (1)Erlotinib (1)
      Investigator-assessed PFS while patient was receiving first TKI60 wk28 wk16 wk8 wk16 wk5 wk28 wk18 wk
      No. additional TKIs10211151
      Additional TKIs (investigator-assessed PFS)Ceritinib (unknown)N/ACeritinib (12 wk) Alectinib (ongoing response at 28 wk)Ceritinib (ongoing response at 80 wk)Alectinib (24 wk)Alectinib (6 wk)Erlotinib (16 wk) Afatinib (4 wk) Icotinib (6 wk) Afatinib + cetuximab (28 wk) Osimertinib (52 wk)Osimertinib (12 wk)
      Survival outcome
      Clinical statusAlive 5 y after diagnosisDied 2 y after diagnosisAlive 2.5 y after diagnosisAlive 3 y after diagnosisAlive 2.5 y after diagnosisAlive 6 mo after diagnosisAlive ≥5 y after diagnosisAlive 11 mo after diagnosis
      PFS, progression-free survival; N/A, not applicable.

      Discussion

      Worldwide, lung cancer is the most common and most lethal malignancy.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics: 2015.
      Although a diagnosis of lung cancer during pregnancy is a rare occurrence,
      • Peccatori F.A.
      • Azim Jr., H.A.
      • Orecchia R.
      • et al.
      Cancer, pregnancy, and fertility: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up.
      the incidence is thought to be increasing—a finding largely attributed to the prevalence of smoking among young women and the increasing incidence of pregnancy at later reproductive age.
      • Pavlidis N.
      Lung cancer during pregnancy: an emerging issue.
      In this report, we describe a single-institution, retrospective analysis in which we identified eight patients in whom NSCLC was diagnosed during pregnancy or the peripartum period, all of whom had limited or no prior tobacco exposure. Our observations, and similar findings in previous reports, suggest that never-smokers may comprise a relatively high proportion of those in whom NSCLC is diagnosed during pregnancy or the peripartum period.
      • Pentheroudakis G.
      • Pavlidis N.
      Gastrointestinal, urologic and lung malignancies during pregnancy.
      These findings suggest that risk factors beyond tobacco exposure might predispose to the development of NSCLC during pregnancy and the peripartum period.
      Oncogenic driver mutations were present in all eight identified cases of NSCLC in pregnancy or the peripartum period. Most published cases of NSCLC diagnosed during pregnancy in never- or light smokers with molecular testing available harbored EGFR mutations.
      • Lee C.H.
      • Liam C.K.
      • Pang Y.K.
      • et al.
      Successful pregnancy with epidermal growth factor receptor tyrosine kinase inhibitor treatment of metastatic lung adenocarcinoma presenting with respiratory failure.
      • Rivas G.
      • Llinas N.
      • Bonilla C.
      • et al.
      Use of erlotinib throughout pregnancy: a case-report of a patient with metastatic lung adenocarcinoma.
      • Ji Y.
      • Schwartz J.
      • Hartford A.
      • et al.
      Successful treatment of non-small cell lung cancer with erlotinib throughout pregnancy.
      • Gil S.
      • Goetgheluck J.
      • Paci A.
      • et al.
      Efficacy and safety of gefitinib during pregnancy: case report and literature review.
      In our series, however, among the different molecular subgroups, ALK-positive NSCLC predominated. This discrepancy may be explained by the rarity of diagnosis of NSCLC during pregnancy or the peripartum period, the relatively recent identification of ALK as an oncogenic driver, younger age of patients with ALK-positive NSCLC relative to other genotypes, variation in frequency of testing for ALK rearrangements across institutions, referral bias, and reporting bias. Establishing a correlation between molecular genotype and development of NSCLC during pregnancy or the peripartum period is challenging because of the low incidence of NSCLC diagnosed among pregnant women. In our series, however, a comparison of ALK-negative NSCLC with ALK-positive NSCLC in women of childbearing age was suggestive of a trend toward an association between ALK rearrangement and a higher likelihood of diagnosis of NSCLC during pregnancy or the peripartum period.
      Most previously published reports of NSCLC during pregnancy predated routine molecular genotyping and, as such, relied on chemotherapy for systemic treatment. Treatment with TKIs may account for the improved outcomes seen in our series and recently published case reports.
      • Lee C.H.
      • Liam C.K.
      • Pang Y.K.
      • et al.
      Successful pregnancy with epidermal growth factor receptor tyrosine kinase inhibitor treatment of metastatic lung adenocarcinoma presenting with respiratory failure.
      • Rivas G.
      • Llinas N.
      • Bonilla C.
      • et al.
      Use of erlotinib throughout pregnancy: a case-report of a patient with metastatic lung adenocarcinoma.
      • Ji Y.
      • Schwartz J.
      • Hartford A.
      • et al.
      Successful treatment of non-small cell lung cancer with erlotinib throughout pregnancy.
      • Gil S.
      • Goetgheluck J.
      • Paci A.
      • et al.
      Efficacy and safety of gefitinib during pregnancy: case report and literature review.
      • Neves I.
      • Mota P.C.
      • Hespanhol V.P.
      Lung cancer during pregnancy: an unusual case.
      • Sariman N.
      • Levent E.
      • Yener N.A.
      • et al.
      Lung cancer and pregnancy.
      Indeed, most of the patients reported in our series are alive more than 2 years after their lung cancer diagnosis (see Table 3). Little, however, is known about the safety of targeted agents during pregnancy. Several reports of successful use of EGFR TKIs during pregnancy have recently been published.
      • Lee C.H.
      • Liam C.K.
      • Pang Y.K.
      • et al.
      Successful pregnancy with epidermal growth factor receptor tyrosine kinase inhibitor treatment of metastatic lung adenocarcinoma presenting with respiratory failure.
      • Rivas G.
      • Llinas N.
      • Bonilla C.
      • et al.
      Use of erlotinib throughout pregnancy: a case-report of a patient with metastatic lung adenocarcinoma.
      • Ji Y.
      • Schwartz J.
      • Hartford A.
      • et al.
      Successful treatment of non-small cell lung cancer with erlotinib throughout pregnancy.
      • Gil S.
      • Goetgheluck J.
      • Paci A.
      • et al.
      Efficacy and safety of gefitinib during pregnancy: case report and literature review.
      • Zambelli A.
      • Prada G.A.
      • Fregoni V.
      • et al.
      Erlotinib administration for advanced non-small cell lung cancer during the first 2 months of unrecognized pregnancy.
      These reports demonstrate that despite transplacental transfer of erlotinib and gefitinib, there is limited accumulation of the TKIs.
      • Ji Y.
      • Schwartz J.
      • Hartford A.
      • et al.
      Successful treatment of non-small cell lung cancer with erlotinib throughout pregnancy.
      • Gil S.
      • Goetgheluck J.
      • Paci A.
      • et al.
      Efficacy and safety of gefitinib during pregnancy: case report and literature review.
      • Jovelet C.
      • Seck A.
      • Mir O.
      • et al.
      Variation in transplacental transfer or tyrosine kinase inhibitors in the human perfused cotyledon model.
      Moreover, one study suggests that gefitinib may be preferable to erlotinib for use in pregnant patients with EGFR-mutant NSCLC as erlotinib may cross the placenta at a higher rate than gefitinib does.
      • Jovelet C.
      • Seck A.
      • Mir O.
      • et al.
      Variation in transplacental transfer or tyrosine kinase inhibitors in the human perfused cotyledon model.
      To our knowledge, there are no published reports of treatment with ALK inhibitors during pregnancy. There are, however, two published cases of ALK-positive NSCLC diagnosed in patients during pregnancy or the peripartum period who were treated with crizotinib after delivery, in both cases after disease progression while they were receiving chemotherapy.
      • Neves I.
      • Mota P.C.
      • Hespanhol V.P.
      Lung cancer during pregnancy: an unusual case.
      • Sariman N.
      • Levent E.
      • Yener N.A.
      • et al.
      Lung cancer and pregnancy.
      Reassuringly, review of the eight cases in our series suggests that for women whose NSCLC is diagnosed late in gestation, it may be possible to delay TKI treatment for a brief period until after delivery.
      Interestingly, five of the eight patients had only brief responses to TKI treatment. In contrast, the clinical outcomes of pregnant patients with EGFR–mutant and ALK-positive NSCLC previously reported in the literature were comparable to those reported for nonpregnant patients.
      • Lee C.H.
      • Liam C.K.
      • Pang Y.K.
      • et al.
      Successful pregnancy with epidermal growth factor receptor tyrosine kinase inhibitor treatment of metastatic lung adenocarcinoma presenting with respiratory failure.
      • Ji Y.
      • Schwartz J.
      • Hartford A.
      • et al.
      Successful treatment of non-small cell lung cancer with erlotinib throughout pregnancy.
      • Neves I.
      • Mota P.C.
      • Hespanhol V.P.
      Lung cancer during pregnancy: an unusual case.
      • Sariman N.
      • Levent E.
      • Yener N.A.
      • et al.
      Lung cancer and pregnancy.
      It is possible that the shorter PFS in this series may be confounded by additional factors, including diagnostic delays in two cases (cases 6 and 8). Alternatively, a diagnosis of NSCLC during pregnancy or the peripartum period may predispose to a particularly aggressive clinical course. Notably, three of the four patients with short PFS while receiving crizotinib experienced central nervous system (CNS) progression. The CNS has previously been identified as a sanctuary site in patients with ALK-rearranged NSCLC on account of the pharmacokinetics of crizotinib.
      • Costa D.B.
      • Shaw A.T.
      • Ou S.H.
      • et al.
      Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases.
      Patient 3 went on to have a durable response on the CNS-penetrant ALK-inhibitor alectinib. Patient 4 underwent stereotactic radiosurgery and continues to respond to ceritinib at 20 months. Despite the reduced PFS of patients while receiving targeted agents, the patients in this series had improved overall survival compared with those in case reports of patients treated with chemotherapy. This may be a reflection of the clinical development of active next-generation TKIs in patients who have progressed while receiving initial TKIs. Indeed, seven of the eight patients were treated with additional TKIs.
      Although this analysis represents observations based on patients seen at a single institution and is limited by the small number of cases identified, the findings reinforce current guidelines, which recommend that molecular genotyping be performed for all patients with metastatic nonsquamous lung cancer. On the basis of our experience and review of recent case reports, molecular studies for patients whose lung cancer is diagnosed during pregnancy or the peripartum period should at a minimum include testing for EGFR mutations and ALK and ROS1 rearrangements. Outcomes after a diagnosis of NSCLC during pregnancy or the peripartum period may be improved in women treated with genotype-specific agents compared with previously observed outcomes with chemotherapy in an unselected population.

      Acknowledgments

      This work was supported by grants from the National Cancer Institute (5R01CA164273, to Dr. Shaw) and the National Foundation for Cancer Research (to Dr. Shaw) and by Be a Piece of the Solution and LungStrong.

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