•Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.•Targetable mutations may lead to new therapies in gynecologic cancer treatment.•Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.•Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.•Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations

Alvarez, Edwin A

Hanft, Wyatt J

Kennedy, Vanessa A

Shepherd-Littlejohn, Amanda L

English

Shepherd-Littlejohn, Amanda

Hanft, Wyatt

Kennedy, Vanessa

Alvarez, Edwin

eScholarship - University of California

UCSFUC San Francisco Previously Published WorksTitleAfatinib use in recurrent epithelial ovarian carcinoma.Permalinkhttps://escholarship.org/uc/item/49d873dcAuthorsShepherd-Littlejohn, AmandaHanft, WyattKennedy, Vanessaet al.Publication Date2019-08-01DOI10.1016/j.gore.2019.07.001 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaContents lists available at ScienceDirectGynecologic Oncology Reportsjournal homepage: www.elsevier.com/locate/gynorCase reportAfatinib use in recurrent epithelial ovarian carcinomaAmanda L. Shepherd-Littlejohna,⁎, Wyatt J. Hanftb,e, Vanessa A. Kennedyc, Edwin A. Alvarezda Department of Gynecologic Oncology, NYU-Winthrop, Mineola, NY,USAb School of Public Health, UC Berkeley, Berkeley, CA,USAc Department of Gynecologic Oncology, UC Davis, Sacramento, CA,USAdDepartment of Gynecologic Oncology, UC San Francisco, San Francisco, CA,USAe School of Medicine, UC Davis, Sacramento, CA,USAA R T I C L E I N F OKeywords:Molecular tumor testingTargeting agentsOvarian cancerHER2/neuERBB2Afatinib1. Patient case41 year old germline and somatic BRCA negative Caucasian femaleunderwent a total abdominal hysterectomy and bilateral salpingo-oo-phorectomy for a pelvic mass at the age of 34. Pathology revealed aserous borderline tumor. The patient presented two years later withnausea, abdominal pain, and bloating. CT scan revealed a 3 cm mass onthe anterior abdominal wall and a 2 cm mass at the vaginal cuff. Sheunderwent a secondary optimal tumor debulking with implants re-moved from the anterior abdominal wall, rectum, sigmoid colon, va-ginal cuff, and stomach. Pathology showed high grade serous carci-noma in all tumor implants. She received carboplatin (AUC 6) and nab-paclitaxel (260mg/m2) every 3 weeks for a total of 6 cycles. Nab-pa-clitaxel was given after the patient had an allergic reaction to her firstdose of paclitaxel. A year after completing chemotherapy, an increasingCA-125 and CT scan revealed intra-abdominal tumor recurrence. Sheunderwent 3 cycles of carboplatin (AUC 6) and liposomal doxorubicin(50mg/m2) with persistently elevated CA-125 levels. Her regimen waschanged to 6 cycles of nab-paclitaxel (260mg/m2) and bevacizumab(15mg/m2) with normalization of her CA-125 level and no residualtumor. Nine months later, the patient presented with intra-abdominalrecurrence. She was given 4 cycles of carboplatin (AUC 6) and gemci-tabine (1000mg/m2) and maintenance q3week topotecan (1.5 mg/m2).After a year, CA-125 levels started to rise and single agent liposomaldoxorubicin was started with subsequent maintenance aromatase in-hibitor, Letrozole. Patient was ineligible for clinical trials due torecurrence in the colon. She developed vaginal bleeding and hadbiopsy-confirmed recurrent high grade serous carcinoma at the vaginalcuff and sigmoid colon. Biopsies were sent for genetic sequencing whichshowed an activating HER2/neu alteration (ERBB2 G776_V777).Genomic results were discussed at a multi-disciplinary molecular tumorboard and afatinib was recommended. The patient started on afatinib(40mg PO daily) and had a significant decrease in her CA-125, decreasein the size of her vaginal tumor, and resolution of her bleeding. Thepatient experienced Grade 1 nausea and a Grade 2 dermatologic rashbut was able to continue on afatinib. The patient had a progression freeinterval of ten months on afatinib. The decision was made to restartnab-paclitaxel (100mg/m2) and bevacizumab (15mg/m2) after an in-crease in CA-125. The patient has continued on maintenance nab-pa-clitaxel for the past six months and has had stable CA-125 levels.2. DiscussionGreat efforts are being made to advance the treatment of ovariancancer but this malignancy is still the 5th leading cause of cancer-re-lated death among women in the United States (La Vecchia et al.,2017). Serous ovarian carcinomas (SOC) comprise 40% of ovarianneoplasms and are the most common form of this malignancy (LaVecchia et al., 2017). The lack of obvious symptoms until advancedstages and the high rate of recurrence greatly contribute to the low(36%) 5-year survival rate of patients with SOC (La Vecchia et al.,2017). In light of this data, new approaches to ovarian cancer treatmenthttps://doi.org/10.1016/j.gore.2019.07.001Received 6 April 2019; Received in revised form 27 June 2019; Accepted 1 July 2019⁎ Corresponding author. 99 Gold Street, Apt. PH-C, Brooklyn, NY 11201,USA.E-mail address: amanda.shepherd-littlejohn@nyulangone.org (A.L. Shepherd-Littlejohn).Gynecologic Oncology Reports 29 (2019) 70–72Available online 03 July 20192352-5789/ © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).Tare necessary.Primary surgical resection is considered the standard treatment forSOC, with adjuvant chemotherapy offered to patients with Stage 1Cdisease or greater (Kampan et al., 2015). The current standard che-motherapy regimen consists of intravenously administered paclitaxel(175mg/m2) and carboplatin (AUC 5–7.5) q3 weeks for 6 cycles(Kampan et al., 2015). Approximately 60% of ovarian cancer patientswill respond to initial treatment with combined paclitaxel-carboplatin,yet the median progression-free survival (PFS) is only 15months(Kampan et al., 2015). The efficacy of platinum regimens is dependenton the treatment-free interval. Patients develop greater platinum re-sistance, and therefore lower response rates (RR), with shorter intervalsbetween primary therapy and recurrence (Kampan et al., 2015).The field of targeted therapies for the treatment of EOC has grownsignificantly in the last ten years. Anti-angiogenic agents are a largepart of this expanding field, with bevacizumab being the most wellstudied.The human epidermal growth factor receptor-2 gene (HER-2/ERBB2) represents another possible target for ovarian cancer based onits successful use in other malignancies. It encodes tyrosine kinase andis member of the ERBB receptor family. Dimerization of HER-2 and anyof the ERBB receptors activates a series of signal transduction pathwaysinvolved in cellular proliferation, differentiation, and migration (Yanet al., 2014). Due to the nature of this receptor, protein overexpression,gene amplification, and gene mutations induce rapid tumor growth(Yan et al., 2014).HER-2 aberrations are common to many tumor types includingbreast, colon, endometrium, and lung. Observed frequency of HER-2positivity in ovarian cancer varies with a range of 1.8–76% (Serrano-Olvera et al., 2006). Review of molecular tumor data from GOG-111and GOG-9404 showed HER-2 overexpression in approximately 7% ofEOC cases (Farley et al., 2009) and as high as 12% in serous histologies(Farley et al., 2009). In these clinical study populations, regardless ofcopy number, ERBB2 amplification was not correlated with tumorstage, tumor histology, overall survival (OS), or sensitivity to platinum-based chemotherapy (Farley et al., 2009).HER-2 overexpressing tumors are targetable using a variety of anti-ERBB2 drugs which are currently approved for breast, stomach, andlung cancers. Non-small cell lung cancer (NSCLC) is now treatable usingafatinib. This ATP-competitive, aniline-quinazoline derivative bindsand irreversibly inhibits signaling from EGFR, HER-2, and HER-4.Downregulating HER-2 and EGFR phosphorylation inhibits downstreamsignaling cascades and induces anti-proliferative effects through cellcycle G1 arrest and apoptotic cell death. Afatinib is approved asmonotherapy for treatment of locally advanced or metastatic NSCLChaving non-resistant EGFR mutations (https://www.accessda-ta.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf, n.d.). Asshown in the LUX-LUNG 3 trial, continuous daily dosing of afatinib, at40–50mg/day in the aforementioned NSCLC patient groups with EGFRmutation-positive Del19, was found to significantly increase RR andPFS in comparison to the standard six cycle cisplatin-pemetrexed che-motherapy regimen (Sequist et al., 2013).With the impressive efficacy of HER-2 targeting therapies in breast,gastric, and lung cancers, attempts are being made to achieve similarefficacy for ovarian cancer. Trastuzumab, a HER-2 monoclonal anti-body that binds the extracellular domain of EGFR, showed success inthe treatment of HER-2 positive breast cancer. Due to its efficacy, theGynecologic Oncology Group initiated a phase II trial of single agenttrastuzumab for patients with recurrent or refractory ovarian carci-noma. Unfortunately, the low response rate of 7.3% limits the utility ofthis agent as a monotherapy (Bookman et al., 2003). Similarly, pertu-zumab, another HER-2 antibody used in the treatment of breast cancers,was found to significantly increase RR and PFS when combined withgemcitabine in platinum-resistant ovarian cancers (Makhija et al.,2010).The effectiveness of afatinib likely depends on a number of differentclinical and molecular factors that have yet to be identified. As an ex-ample, the Carvajal-Hausdorf study identified cases of HER2 amplifi-cation showing differing levels of intracellular (ICD) and extracellulardomains (ECD) (Carvajal-Hausdorf et al., 2017). Because HER2 targetedagents are directed against the HER2 ICD or ECD, these findings suggestthat targeted HER2 agents may need to be tailored to the specific do-main levels present.For the patient in this case, afatinib was chosen as treatment due tothe presence of an activating mutation in HER2. This use is an extra-polation of the results from the LUX-Lung trial in NSCLC. We havepresented this case to demonstrate anecdotal effectiveness of targetingHER2/neu activation in patients with ovarian cancer and a HER2 ac-tivating tumor mutation.3. ConclusionCommercially available genomic sequencing can be used to guideindividual treatment plans for primary or recurrent malignancies andshould be based on the activating mutations present in the tumor.Her2/neu mutations are an effective target in lung cancers and afatinibis an effective targeting agent. Larger clinical trials are needed to assessthe effectiveness of afatinib in ovarian cancer patients and to identifythe specific sub-populations in which it may be most effective. Due tothe rarity of this mutation in ovarian cancer, this may require a baskettrial study that would assess use of afatinib or other HER2 targetingsmall molecule inhibitors in tumor types with activating HER2 muta-tion.Declaration of Competing InterestsDr. Amanda Shepherd-Littlejohn, Wyatt Hanft, Dr. VanessaKennedy, and Dr. Edwin Alvarez have no financial or personal conflictsof interest in producing this manuscript. Dr. Shepherd-Littlejohn, WyattHanft, Dr. Kennedy, and Dr. Alvarez have nothing to disclose.Author contributionsWyatt Hanft, MPH, conceived the idea, collected patient data, andwrote the first draft of the paper.Dr. Amanda Shepherd-Littlejohn collected patient data, developedthe discussion and contribution section of the paper, and edited thepaper after the first draft. Dr. Shepherd-Littlejohn is also responsible forsubmission and is the corresponding author.Dr. Vanessa Kennedy and Dr. Edwin Alvarez conceived the idea,were the final editors of the paper, and acted as mentors during theproduction of the manuscript.ReferencesBookman, M.A., et al., 2003. Evaluation of monoclonal humanized anti-HER2 antibody,Trastuzumab, in patients with recurrent or refractory ovarian or primary peritonealcarcinoma with overexpression of HER2: a phase II trial of the Gynecologic OncologyGroup. J. Clin. Oncol. 21 (2), 283–290.Carvajal-Hausdorf, D.E., et al., 2017. Objective, domain-specific HER2 measurement inuterine and ovarian serous carcinomas and its clinical significance. Gynecol. Oncol.145 (1), 154–158.Farley, J., et al., 2009. Associations between ERBB2 amplification and progression-freesurvival and overall survival in advanced stage, suboptimally-resected epithelialovarian cancers: a Gynecologic Oncology Group Study. Gynecol. Oncol. 113 (3),341–347.https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf.Kampan, N.C., et al., 2015. Paclitaxel and its evolving role in the Management of OvarianCancer. Biomed. Res. Int., 413076.La Vecchia, C., et al., 2017. Ovarian cancer: epidemiology and risk factors. Eur. J. CancerPrev. 26 (1), 55–62.Makhija, S., et al., 2010. Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J. Clin.Oncol. 28 (7), 1215–1223.Sequist, L.V., et al., 2013. Phase III study of afatinib or cisplatin plus pemetrexed inpatients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol.31 (27), 3327–3334.A.L. Shepherd-Littlejohn, et al. Gynecologic Oncology Reports 29 (2019) 70–7271Serrano-Olvera, A., et al., 2006. Prognostic, predictive and therapeutic implications ofHER2 in invasive epithelial ovarian cancer. Cancer Treat. Rev. 32 (3), 180–190.Yan, M., et al., 2014. HER2 aberrations in cancer: implications for therapy. Cancer Treat.Rev. 40 (6), 770–780.A.L. Shepherd-Littlejohn, et al. Gynecologic Oncology Reports 29 (2019) 70–7272

Afatinib use in recurrent epithelial ovarian carcinoma.

UCSFUC San Francisco Previously Published WorksTitleAfatinib use in recurrent epithelial ovarian carcinomaPermalinkhttps://escholarship.org/uc/item/7t45p3z8AuthorsShepherd-Littlejohn, Amanda LHanft, Wyatt JKennedy, Vanessa Aet al.Publication Date2019-08-01DOI10.1016/j.gore.2019.07.001 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaContents lists available at ScienceDirectGynecologic Oncology Reportsjournal homepage: www.elsevier.com/locate/gynorCase reportAfatinib use in recurrent epithelial ovarian carcinomaAmanda L. Shepherd-Littlejohna,⁎, Wyatt J. Hanftb,e, Vanessa A. Kennedyc, Edwin A. Alvarezda Department of Gynecologic Oncology, NYU-Winthrop, Mineola, NY,USAb School of Public Health, UC Berkeley, Berkeley, CA,USAc Department of Gynecologic Oncology, UC Davis, Sacramento, CA,USAdDepartment of Gynecologic Oncology, UC San Francisco, San Francisco, CA,USAe School of Medicine, UC Davis, Sacramento, CA,USAA R T I C L E I N F OKeywords:Molecular tumor testingTargeting agentsOvarian cancerHER2/neuERBB2Afatinib1. Patient case41 year old germline and somatic BRCA negative Caucasian femaleunderwent a total abdominal hysterectomy and bilateral salpingo-oo-phorectomy for a pelvic mass at the age of 34. Pathology revealed aserous borderline tumor. The patient presented two years later withnausea, abdominal pain, and bloating. CT scan revealed a 3 cm mass onthe anterior abdominal wall and a 2 cm mass at the vaginal cuff. Sheunderwent a secondary optimal tumor debulking with implants re-moved from the anterior abdominal wall, rectum, sigmoid colon, va-ginal cuff, and stomach. Pathology showed high grade serous carci-noma in all tumor implants. She received carboplatin (AUC 6) and nab-paclitaxel (260mg/m2) every 3 weeks for a total of 6 cycles. Nab-pa-clitaxel was given after the patient had an allergic reaction to her firstdose of paclitaxel. A year after completing chemotherapy, an increasingCA-125 and CT scan revealed intra-abdominal tumor recurrence. Sheunderwent 3 cycles of carboplatin (AUC 6) and liposomal doxorubicin(50mg/m2) with persistently elevated CA-125 levels. Her regimen waschanged to 6 cycles of nab-paclitaxel (260mg/m2) and bevacizumab(15mg/m2) with normalization of her CA-125 level and no residualtumor. Nine months later, the patient presented with intra-abdominalrecurrence. She was given 4 cycles of carboplatin (AUC 6) and gemci-tabine (1000mg/m2) and maintenance q3week topotecan (1.5 mg/m2).After a year, CA-125 levels started to rise and single agent liposomaldoxorubicin was started with subsequent maintenance aromatase in-hibitor, Letrozole. Patient was ineligible for clinical trials due torecurrence in the colon. She developed vaginal bleeding and hadbiopsy-confirmed recurrent high grade serous carcinoma at the vaginalcuff and sigmoid colon. Biopsies were sent for genetic sequencing whichshowed an activating HER2/neu alteration (ERBB2 G776_V777).Genomic results were discussed at a multi-disciplinary molecular tumorboard and afatinib was recommended. The patient started on afatinib(40mg PO daily) and had a significant decrease in her CA-125, decreasein the size of her vaginal tumor, and resolution of her bleeding. Thepatient experienced Grade 1 nausea and a Grade 2 dermatologic rashbut was able to continue on afatinib. The patient had a progression freeinterval of ten months on afatinib. The decision was made to restartnab-paclitaxel (100mg/m2) and bevacizumab (15mg/m2) after an in-crease in CA-125. The patient has continued on maintenance nab-pa-clitaxel for the past six months and has had stable CA-125 levels.2. DiscussionGreat efforts are being made to advance the treatment of ovariancancer but this malignancy is still the 5th leading cause of cancer-re-lated death among women in the United States (La Vecchia et al.,2017). Serous ovarian carcinomas (SOC) comprise 40% of ovarianneoplasms and are the most common form of this malignancy (LaVecchia et al., 2017). The lack of obvious symptoms until advancedstages and the high rate of recurrence greatly contribute to the low(36%) 5-year survival rate of patients with SOC (La Vecchia et al.,2017). In light of this data, new approaches to ovarian cancer treatmenthttps://doi.org/10.1016/j.gore.2019.07.001Received 6 April 2019; Received in revised form 27 June 2019; Accepted 1 July 2019⁎ Corresponding author. 99 Gold Street, Apt. PH-C, Brooklyn, NY 11201,USA.E-mail address: amanda.shepherd-littlejohn@nyulangone.org (A.L. Shepherd-Littlejohn).Gynecologic Oncology Reports 29 (2019) 70–72Available online 03 July 20192352-5789/ © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).Tare necessary.Primary surgical resection is considered the standard treatment forSOC, with adjuvant chemotherapy offered to patients with Stage 1Cdisease or greater (Kampan et al., 2015). The current standard che-motherapy regimen consists of intravenously administered paclitaxel(175mg/m2) and carboplatin (AUC 5–7.5) q3 weeks for 6 cycles(Kampan et al., 2015). Approximately 60% of ovarian cancer patientswill respond to initial treatment with combined paclitaxel-carboplatin,yet the median progression-free survival (PFS) is only 15months(Kampan et al., 2015). The efficacy of platinum regimens is dependenton the treatment-free interval. Patients develop greater platinum re-sistance, and therefore lower response rates (RR), with shorter intervalsbetween primary therapy and recurrence (Kampan et al., 2015).The field of targeted therapies for the treatment of EOC has grownsignificantly in the last ten years. Anti-angiogenic agents are a largepart of this expanding field, with bevacizumab being the most wellstudied.The human epidermal growth factor receptor-2 gene (HER-2/ERBB2) represents another possible target for ovarian cancer based onits successful use in other malignancies. It encodes tyrosine kinase andis member of the ERBB receptor family. Dimerization of HER-2 and anyof the ERBB receptors activates a series of signal transduction pathwaysinvolved in cellular proliferation, differentiation, and migration (Yanet al., 2014). Due to the nature of this receptor, protein overexpression,gene amplification, and gene mutations induce rapid tumor growth(Yan et al., 2014).HER-2 aberrations are common to many tumor types includingbreast, colon, endometrium, and lung. Observed frequency of HER-2positivity in ovarian cancer varies with a range of 1.8–76% (Serrano-Olvera et al., 2006). Review of molecular tumor data from GOG-111and GOG-9404 showed HER-2 overexpression in approximately 7% ofEOC cases (Farley et al., 2009) and as high as 12% in serous histologies(Farley et al., 2009). In these clinical study populations, regardless ofcopy number, ERBB2 amplification was not correlated with tumorstage, tumor histology, overall survival (OS), or sensitivity to platinum-based chemotherapy (Farley et al., 2009).HER-2 overexpressing tumors are targetable using a variety of anti-ERBB2 drugs which are currently approved for breast, stomach, andlung cancers. Non-small cell lung cancer (NSCLC) is now treatable usingafatinib. This ATP-competitive, aniline-quinazoline derivative bindsand irreversibly inhibits signaling from EGFR, HER-2, and HER-4.Downregulating HER-2 and EGFR phosphorylation inhibits downstreamsignaling cascades and induces anti-proliferative effects through cellcycle G1 arrest and apoptotic cell death. Afatinib is approved asmonotherapy for treatment of locally advanced or metastatic NSCLChaving non-resistant EGFR mutations (https://www.accessda-ta.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf, n.d.). Asshown in the LUX-LUNG 3 trial, continuous daily dosing of afatinib, at40–50mg/day in the aforementioned NSCLC patient groups with EGFRmutation-positive Del19, was found to significantly increase RR andPFS in comparison to the standard six cycle cisplatin-pemetrexed che-motherapy regimen (Sequist et al., 2013).With the impressive efficacy of HER-2 targeting therapies in breast,gastric, and lung cancers, attempts are being made to achieve similarefficacy for ovarian cancer. Trastuzumab, a HER-2 monoclonal anti-body that binds the extracellular domain of EGFR, showed success inthe treatment of HER-2 positive breast cancer. Due to its efficacy, theGynecologic Oncology Group initiated a phase II trial of single agenttrastuzumab for patients with recurrent or refractory ovarian carci-noma. Unfortunately, the low response rate of 7.3% limits the utility ofthis agent as a monotherapy (Bookman et al., 2003). Similarly, pertu-zumab, another HER-2 antibody used in the treatment of breast cancers,was found to significantly increase RR and PFS when combined withgemcitabine in platinum-resistant ovarian cancers (Makhija et al.,2010).The effectiveness of afatinib likely depends on a number of differentclinical and molecular factors that have yet to be identified. As an ex-ample, the Carvajal-Hausdorf study identified cases of HER2 amplifi-cation showing differing levels of intracellular (ICD) and extracellulardomains (ECD) (Carvajal-Hausdorf et al., 2017). Because HER2 targetedagents are directed against the HER2 ICD or ECD, these findings suggestthat targeted HER2 agents may need to be tailored to the specific do-main levels present.For the patient in this case, afatinib was chosen as treatment due tothe presence of an activating mutation in HER2. This use is an extra-polation of the results from the LUX-Lung trial in NSCLC. We havepresented this case to demonstrate anecdotal effectiveness of targetingHER2/neu activation in patients with ovarian cancer and a HER2 ac-tivating tumor mutation.3. ConclusionCommercially available genomic sequencing can be used to guideindividual treatment plans for primary or recurrent malignancies andshould be based on the activating mutations present in the tumor.Her2/neu mutations are an effective target in lung cancers and afatinibis an effective targeting agent. Larger clinical trials are needed to assessthe effectiveness of afatinib in ovarian cancer patients and to identifythe specific sub-populations in which it may be most effective. Due tothe rarity of this mutation in ovarian cancer, this may require a baskettrial study that would assess use of afatinib or other HER2 targetingsmall molecule inhibitors in tumor types with activating HER2 muta-tion.Declaration of Competing InterestsDr. Amanda Shepherd-Littlejohn, Wyatt Hanft, Dr. VanessaKennedy, and Dr. Edwin Alvarez have no financial or personal conflictsof interest in producing this manuscript. Dr. Shepherd-Littlejohn, WyattHanft, Dr. Kennedy, and Dr. Alvarez have nothing to disclose.Author contributionsWyatt Hanft, MPH, conceived the idea, collected patient data, andwrote the first draft of the paper.Dr. Amanda Shepherd-Littlejohn collected patient data, developedthe discussion and contribution section of the paper, and edited thepaper after the first draft. Dr. Shepherd-Littlejohn is also responsible forsubmission and is the corresponding author.Dr. Vanessa Kennedy and Dr. Edwin Alvarez conceived the idea,were the final editors of the paper, and acted as mentors during theproduction of the manuscript.ReferencesBookman, M.A., et al., 2003. Evaluation of monoclonal humanized anti-HER2 antibody,Trastuzumab, in patients with recurrent or refractory ovarian or primary peritonealcarcinoma with overexpression of HER2: a phase II trial of the Gynecologic OncologyGroup. J. Clin. Oncol. 21 (2), 283–290.Carvajal-Hausdorf, D.E., et al., 2017. Objective, domain-specific HER2 measurement inuterine and ovarian serous carcinomas and its clinical significance. Gynecol. Oncol.145 (1), 154–158.Farley, J., et al., 2009. Associations between ERBB2 amplification and progression-freesurvival and overall survival in advanced stage, suboptimally-resected epithelialovarian cancers: a Gynecologic Oncology Group Study. Gynecol. Oncol. 113 (3),341–347.https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf.Kampan, N.C., et al., 2015. Paclitaxel and its evolving role in the Management of OvarianCancer. Biomed. Res. Int., 413076.La Vecchia, C., et al., 2017. Ovarian cancer: epidemiology and risk factors. Eur. J. CancerPrev. 26 (1), 55–62.Makhija, S., et al., 2010. Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J. Clin.Oncol. 28 (7), 1215–1223.Sequist, L.V., et al., 2013. Phase III study of afatinib or cisplatin plus pemetrexed inpatients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol.31 (27), 3327–3334.A.L. Shepherd-Littlejohn, et al. Gynecologic Oncology Reports 29 (2019) 70–7271Serrano-Olvera, A., et al., 2006. Prognostic, predictive and therapeutic implications ofHER2 in invasive epithelial ovarian cancer. Cancer Treat. Rev. 32 (3), 180–190.Yan, M., et al., 2014. HER2 aberrations in cancer: implications for therapy. Cancer Treat.Rev. 40 (6), 770–780.A.L. Shepherd-Littlejohn, et al. Gynecologic Oncology Reports 29 (2019) 70–7272

Afatinib use in recurrent epithelial ovarian carcinoma

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Afatinib use in recurrent epithelial ovarian carcinoma.

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