T h e n e w e ngl a nd j o u r na l o f m e dic i n e case records of the massachusetts general hospital Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor Case 14-2013: A 70-Year-Old Woman with Vaginal Bleeding Richard T. Penson, M.D., Annekathryn Goodman, M.D., Whitfield B. Growdon, M.D., Darrell R. Borger, Ph.D., Susanna I. Lee, M.D., Ph.D., and Esther Oliva, M.D. Pr esen tation of C a se A 70-year-old woman was seen in the gynecologic cancer center at this hospital From the Divisions of Hematology and because of vaginal bleeding. Oncology (R.T.P., D.R.B.) and Gyneco- logic Oncology (A.G., W.B.G.) and the Approximately 1 month earlier, the patient had noted a brown vaginal discharge; Departments of Radiology (S.I.L.) and Pa- 18 days before she was seen in the gynecologic cancer center, vaginal bleeding had thology (E.O.), Massachusetts General developed. During the week after the onset of bleeding, transabdominal and trans- Hospital; and the Departments of Medi- cine (R.T.P., D.R.B.), Obstetrics, Gynecol- vaginal ultrasonography of the pelvis revealed a normal-size uterus (5.9 cm in ogy, and Reproductive Biology (A.G., length). The endometrial lining was abnormally heterogeneous and thickened, W.B.G.), Radiology (S.I.L.), and Pathology measuring up to 1 cm. The kidneys and ovaries were normal. She saw her gyne- (E.O.), Harvard Medical School — both in Boston. cologist, and an endometrial biopsy was performed. Pathological examination of the specimen showed a poorly differentiated malignant neoplasm, suggestive of N Engl J Med 2013;368:1827-35. DOI: 10.1056/NEJMcpc1209276 malignant mixed müllerian tumor (carcinosarcoma). Copyright © 2013 Massachusetts Medical Society. Twelve days after the endometrial biopsy, the patient saw a gynecologic oncolo- gist in the cancer center of this hospital. She reported no pelvic pain, change in appetite or weight, nausea, or vomiting. She was gravida 3, para 3, with normal spontaneous vaginal deliveries, and she had had laparotomies in the past for evaluation of endometriosis and primary infertility. Her last menstrual period had been 20 years earlier. Eleven years earlier, uterine bleeding had developed, which resolved after endometrial polypectomy. Ten years earlier, a diagnosis of infiltrat- ing ductal carcinoma of the right breast had been made (T2N0); testing for estro- gen receptor (ER) and progesterone receptor (PR) was positive, and immunohisto- chemical staining showed overexpression of human epidermal growth factor receptor type 2 (HER2). Treatment included lumpectomy with sentinel-lymph-node mapping; adjuvant chemotherapy with four cycles of doxorubicin, cyclophospha- mide, and weekly paclitaxel, followed by radiation therapy; and the administration of tamoxifen for 4 years, followed by anastrozole. The patient also had osteoporosis, hypercholesterolemia, and hypothyroidism. Medications included anastrozole (1 mg orally daily), risedronate, atorvastatin, levothyroxine, calcium supplements, glucosamine, chondroitin, aspirin, biotin, and a multivitamin. She was allergic to penicillin and codeine. She lived with her hus- band and did not smoke or drink alcohol. Her parents died of heart disease in their 90s, her maternal grandfather died of pancreatic cancer at 70 years of age, and a n engl j med 368;19 nejm.org may 9, 2013 1827 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on June 13, 2019. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. T h e n e w e ngl a nd j o u r na l o f m e dic i n e maternal uncle died of liver cancer at 60 years of phy (PET-CT) and a meticulous exploratory lapa- age; her brother, children, and grandchildren rotomy are standard practice. were healthy. The big surgical questions for this patient are On examination, the patient was obese, the whether laparoscopy would allow for tumor stag- vital signs were normal, the uterus was small ing and the extent of lymphadenectomy that and mobile, and there were no vulvar, vaginal, or needs to be performed. In one randomized cervical lesions. The remainder of the examina- study, laparoscopy was associated with substan- tion was unremarkable. Routine laboratory tests, tially better overall quality of life and body im- including measurement of the CA-125 level, chest age than was open surgery, and only 21% of the radiography, electrocardiography, a cardiac stress patients who underwent laparoscopy required test, and preoperative cardiac evaluation, were all conversion to laparotomy for full staging.4 Lapa- normal. roscopic hysterectomy does not compromise the Two weeks later, a diagnostic and therapeutic surgical management of uterine cancer.4 procedure was performed and additional man- For this patient with carcinosarcoma, a high- agement decisions were made. ly malignant uterine tumor, laparotomy remains the standard of care. We generally follow the Discussion of M a nagemen t Mayo Clinic practice of not performing lymphad- enectomy if uterine tumors are less than 2 cm in Dr. Annekathryn Goodman: This 70-year-old woman size, are grade 1 or 2, and invade less than 50% presented with postmenopausal bleeding, and an of the myometrium5; however, surgery for carci- endometrial-biopsy specimen showed a malignant nosarcoma routinely includes lymphadenectomy. tumor, probably carcinosarcoma. The underlying This patient underwent total abdominal hyster- cause of abnormal vaginal bleeding is age-depen- ectomy, bilateral salpingo-oophorectomy, bilater- dent. Ten percent of premenopausal women with al pelvic-node dissection, and omentectomy. abnormal bleeding have a malignant tumor. In contrast, 75% of women over 70 years of age with Pathol o gic a l Discussion postmenopausal bleeding have cancer, and the risk rises with age in postmenopausal women.1 Dr. Esther Oliva: The original endometrial-biopsy Postmenopausal vaginal bleeding is the most com- specimen showed a high-grade endometrial car- mon manifestation of carcinosarcoma. Patients cinoma, with areas suggestive of associated ma- with carcinosarcoma also frequently present with lignant mesenchyme. These findings were con- the classic triad of painful postmenopausal bleed- sistent with a malignant mixed müllerian tumor ing, an enlarged uterus, and prolapsed tumor vis- (carcinosarcoma). ible at the cervical os; the triad was not seen in The patient subsequently underwent total hys- this patient. terectomy, bilateral salpingo-oophorectomy, omen- In only a few circumstances is surgery not the tectomy, and bilateral pelvic-lymph-node dissec- primary treatment for uterine cancer — when tion. The uterus measured 8.8 cm by 3.9 cm by there is a desire to preserve fertility, when the 2.8 cm and weighed 78.4 g. An exophytic, ill- operative risk is high, and when the disease is defined, tan-white mass (2.0 cm by 1.5 cm) was unresectable.2 The goals of surgical treatment centered in the right fundus and involved the are excision of all disease with at least a 1-cm anterior and posterior walls. Sectioning showed margin and staging of the tumor. The initial that the tumor deeply invaded the myometrium. spread is to regional lymph nodes; therefore, Microscopical examination showed that the tu- standard treatment is a total abdominal hyster- mor was composed of an intimate admixture of ectomy and bilateral salpingo-oophorectomy with high-grade serous carcinoma and predominantly lymphadenectomy. Endometrial cancers have homologous sarcoma (Fig. 1A), with focal areas several potential patterns of spread: direct inva- of chondrosarcoma (Fig. 1B). The malignant sion and expansion of the primary tumor, lym- epithelial component deeply invaded the myome- phatic invasion, hematogenous spread, and in- trium (to a depth of 2.1 cm in myometrium that traperitoneal dissemination.3 Because metastasis had a depth of 2.3 cm) (Fig. 1C), and areas of is common, preoperative combination positron- lymphovascular invasion (stage IB) were noted emission tomography and computed tomogra- (Fig. 1D). There was no evidence of tumor in the 1828 n engl j med 368;19 nejm.org may 9, 2013 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on June 13, 2019. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital ovaries, fallopian tubes, omentum, or four right and five left pelvic lymph nodes. All margins A B were free of tumor. Diagnostic features of malignant mixed mül- lerian tumor include the finding of a biphasic malignant tumor that is composed of high- grade carcinoma (most commonly endometrioid or serous) and sarcoma that is typically homolo- gous (arising from mesenchymal tissue normally found in the uterus), although in up to 50% of cases (including this case), the tumor has a het- erologous component (most commonly rhabdo- myosarcoma or chondrosarcoma). There is no transition between the epithelial and mesenchy- mal components.6 Tumor stage is the most im- portant prognostic factor in these tumors,7 al- though histologic features also affect outcome. C D The finding of serous or clear-cell carcinoma is associated with a more aggressive course of the disease. Sarcomatous components adversely af- fect the overall prognosis for patients with stage I tumors (the 5-year survival rate is 30% among patients with heterologous elements as compared with 80% among patients with homologous ele- ments); myometrial and lymphovascular invasion are also associated with a poor prognosis.7-9 This patient has all these adverse factors. Although malignant mixed müllerian tumors were initially classified as sarcomas, the latest World Health Organization classification includes them in the category of endometrial carcinomas, since these tumors display genetic alterations Figure 1. Hysterectomy Specimen (Hematoxylin and Eosin). that are common to both the epithelial and the The malignant mixed müllerian tumor is composed of high-grade serous carcinoma, with a pseudoglandular architecture, and high-grade homolo- mesenchymal components.10,11 These alterations gous sarcoma (Panel A). Heterologous sarcomatous elements represented include a high frequency of TP53 mutations, by chondrosarcoma are also present (Panel B). The epithelial component multiple chromosomal gains and losses, up-regu- has invaded the myometrium (Panel C) and some of the lymphatic spaces lation of the AKT–β-catenin pathway (AKT is also (Panel D). known as protein kinase B), amplification of HER2, microsatellite instability, and KRAS muta- tions.12 This tumor is an example of stable epi- Discussion of M a nagemen t thelial-to-mesenchymal transition, a process of cellular transdifferentiation in which epithelial Dr. Richard T. Penson: The term “carcinosarcoma” cells lose polarity and cell-to-cell contacts, reor- was originally described by Rosenstein in 1883, ganize their cytoskeleton, lose expression of and the term “malignant mixed müllerian tu- epithelial markers, and acquire expression of mor” was introduced by Sternberg and colleagues mesenchymal markers. Epithelial-to-mesenchy- in 1954.14 In the past few years, the designation mal transition results from complex signaling, of carcinosarcoma has been favored by the Gyne- including, but not limited to, the switching of cologic Oncology Group (GOG). cadherin subtypes, gain of expression of mesen- Carcinosarcoma requires an integrated ap- chymal markers, and activation of signaling proach that spans multiple medical disciplines, pathways such as transforming growth factor β, but the optimal therapeutic approach for this pa- notch, and hedgehog.13 tient has not been clearly defined. The consider- n engl j med 368;19 nejm.org may 9, 2013 1829 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on June 13, 2019. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. T h e n e w e ngl a nd j o u r na l o f m e dic i n e ations include whether to use radiation, whether A to use adjuvant chemotherapy, and which specific chemotherapy regimen to use (if the decision is made to use chemotherapy). Radiation therapy has been shown to reduce the rates of local re- currence in the pelvis but does not increase sur- vival among patients with carcinosarcoma.15-17 Adjuvant chemotherapy has not been shown to have an effect on recurrence rates or progression- free or overall survival among patients with carcinosarcoma.17 Hormonal therapy is of no use for this patient, since estrogen and proges- terone receptors do not control tumor growth, even though they are typically present in patients with carcinosarcoma. To maximize the potential therapeutic effect for a patient such as this one who has high-risk disease, we have typically used a combination of doxorubicin, paclitaxel, and carboplatin with growth-factor support, administered for three cycles and followed by radiation therapy. The benefit of this strategy over the standard six B cycles of carboplatin and paclitaxel is unknown; however, there is increasing support for the standard six-cycle strategy because of the lack of benefit of more intense chemotherapy for patients such as this one with metastatic disease, as shown in study GOG-209 (ClinicalTrials.gov number, NCT00063999).18,19 Dr. Goodman: The patient was treated with six cycles of adjuvant carboplatin and paclitaxel, fol- lowed by brachytherapy (total dose, 2100 cGy) to the vault of the vagina. CT of the chest, abdomen, and pelvis 1 month after the completion of ther- apy revealed no evidence of cancer in the chest C or upper abdomen but did reveal soft-tissue den- sities in the pelvis that were thought to be re- solving postoperative inflammatory changes. Eleven months after the completion of chemo- therapy, the patient was admitted to another hospital with a 3-day history of dyspnea and leg edema. Dr. Susanna I. Lee: On presentation at the other hospital, CT of the abdomen and pelvis after the administration of intravenous contrast material Figure 2. Abdominopelvic CT Images after the Adminis- (Fig. 2) showed occlusion of the inferior vena cava tration of Oral and Intravenous Contrast Material. by a circumferential retroperitoneal soft-tissue A coronal reconstruction image (Panel A) and axial imag- mass measuring approximately 4 cm in maximal es (Panels B and C) show a retroperitoneal soft-tissue mass (arrows) encircling and occluding the inferior vena dimension and extending from below the renal cava. New subcentimeter liver lesions (arrowheads) are veins to the confluence of the common iliac veins. also seen. These findings suggest tumor recurrence. Two lesions measuring approximately 5 mm in greatest dimension were apparent in the liver. 1830 n engl j med 368;19 nejm.org may 9, 2013 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on June 13, 2019. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital Ventilation–perfusion lung scans showed a low probability of pulmonary emboli. Ultrasono- A B graphic studies confirmed the presence of ex- tensive deep venous thrombosis; CT of the chest with intravenous contrast material revealed no pulmonary emboli or lesions suspicious for meta- static disease. Integrated whole-body 18F-fluorodeoxyglucose (FDG) PET performed with concurrent CT of the chest, abdomen, and pelvis after the adminis- tration of intravenous contrast material (Fig. 3) 11 days later revealed marked FDG avidity in the retroperitoneal mass and liver lesions; the liver lesions had increased in size and number since the previous CT scan. A previously undetected focus of intense tracer uptake was seen in the L2 vertebral body, a finding that was consistent with metastasis. No intrathoracic metastases were seen. Pathol o gic a l Discussion Dr. Oliva: A CT-guided retroperitoneal (aortocaval) lymph-node biopsy was performed. The specimen consisted of fragments of collagenous tissue with C D scant poorly preserved carcinoma cells, findings consistent with recurrence of the malignant mixed müllerian tumor. Dr. Whitfield B. Growdon: Genetic features of this patient’s tumor may be important in the selection of additional treatment. The genetic differential diagnosis is greatly informed by the clinical type of uterine carcinoma. Clinical in- Figure 3. Integrated Whole-Body FDG-PET and CT. vestigators group endometrial cancers into two Frontal (Panel A) and lateral (Panel B) positron-emission tomography (PET) images show avid uptake of 18F-fluorodeoxyglucose (FDG) by the retroperi- types.20 Of all endometrial cancers, 85 to 90% of toneal mass (white arrow) and liver lesions (arrowheads), as well as a hyper- cases are type I, which tend to be early-stage, metabolic focus in the lumbar spine (black arrow). A contrast-enhanced CT with low-grade endometrioid histologic features, image (Panel C) shows liver lesions (arrowheads) that had increased in size manifestation in patients who are young, and an and number since the CT scan that was obtained 11 days earlier. Fusion of an excellent prognosis. In contrast, this patient has FDG-PET scan and a CT image (Panel D) shows a previously undetected hypermetabolic focus in the L2 vertebral body (arrow), a finding that was a type II cancer, which typically has a high his- consistent with metastasis. tologic grade, a spectrum of histologic types (e.g., papillary serous carcinoma, clear-cell car- cinoma, undifferentiated carcinoma, and carci- as compared with the 85% rate observed among nosarcoma), manifestation in older women, and patients with endometrioid tumors.25 Carcino- aggressive behavior.11,21 Only 10 to 15% of uter- sarcoma developed in this patient after she had ine cancers are type II cancers, but they are re- received treatment with tamoxifen.26 Two identi- sponsible for 40 to 50% of deaths from endome- fied risk factors for the development of carcino- trial cancer.22,23 As compared with endometrioid sarcoma are radiation, which increases the risk carcinoma, carcinosarcoma is twice as likely to by a factor of 8, and tamoxifen, which increases be locally advanced and more than twice as the risk by a factor of 2 to 7.27,28 likely to be metastatic at presentation.24 These Specific genetic signatures that may have features most likely explain why carcinosarcoma relevance to the treatment of this patient have is associated with a 5-year overall survival of 29% been shown to be associated with type I and n engl j med 368;19 nejm.org may 9, 2013 1831 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on June 13, 2019. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. T h e n e w e ngl a nd j o u r na l o f m e dic i n e mon in type I cancers, and alterations in TP53 A (encoding tumor protein p53) and HER2 are more Uterine adenocarcinoma Uterine carcinosarcoma common in type II cancers. Activation of PIK3CA 45 (30 patients) (31 patients) (encoding the phosphatidylinositol-4,5-bisphos- 40 phate 3-kinase, catalytic subunit alpha protein) 35 through mutation or amplification is prevalent in 30 both types.18,21,29 Recent data also show that 43% 25 of carcinosarcomas harbor gain-of-function mu- 20 tations in PIK3CA or KRAS in both the carcinoma- 15 tous and sarcomatous compartments.30 In light 10 of these data, genetic testing of this patient’s 5 carcinosarcoma could reveal mutations that 0 would direct her treatment toward innovative on e ied A S 3 N 1 F 1 S N tif 3 C RA P5 TE KT RA NB RAT therapies targeting specific oncogenic pathways. en PI K K P A B TN Nid C Dr. Darrell R. Borger: To personalize cancer treat- Cancer-Gene Mutations ment, it is becoming increasingly important for the clinical evaluation to include highly multi- B plexed tumor genotyping. This is particularly Control Patient without Cancer BRAF NRAS relevant to this patient, in whom recurrent meta- c.1798 c.37 APC static disease developed after she had received PIK3CA APCc.4348 c.3140 PIK3CA c.3340 standard treatment and for whom an alternative CTNNB1 c.1636 treatment was being sought. Testing for this c.101 patient was performed with the use of a cancer- gene mutational platform that has been expand- ed to simultaneously query for 160 site-specific mutations across 15 cancer driver genes (SNaPshot Multiplex System, Applied Biosystems).31 The panel emphasizes known activating point muta- This Patient tions of oncogenes that are relevant for targeted PIK3CA His1047Arg therapeutics. The testing was performed in a (c.3140A→G) laboratory certified under the Clinical Labora- tory Improvements Amendments and is fully validated as a clinical test that is routinely used in our institution to guide treatment decisions. To date, 61 patients with uterine carcinoma have Figure 4. Molecular Genetic Analysis. been tested and mutations have been identified Panel A shAoUwTsH tOheR :frPeeqnusoenncy of cancer-gene mutationRse viidseedntified during in 37. We have observed that the mutational pro- routine cliniFcIaGl UteRsEt:in4g o fo 4f 61 patients at Massachusetts General Hospital in files of uterine adenocarcinomas and uterine carci- whom uterine adenocarcinoma or uterine carcinosarcoma was diagnosed. SIZE nosarcomas overlap at least partially (Fig. 4A). The genotypAinRgT IpSTla:ttfsorm was able to identify driver mutations in 37 of 4 col The initial formalin-fixed, paraffin-embedded these patientsT, YaPnEd: theL irneelativCeo mbuotatio4n-aCl proHf/ilTes are sh2o2pw3n. More than endometrial-biopsy sample from this patient was one mutation was identified in some samples. In Panel B, the portion of the electropherogram obtaAinUeTdH fOroRm, P LmEAuStaEt NioOnTaEl :p rofiling highlights the obtained for mutational profiling. The specimen Figure has been redrawn and type has been reset. PIK3CA c.3140 assay. NucleicP alecaidse f crohemck a c anroenfucllayn. cerous control sample pro- consisted of a large aggregate of tissue frag- duced a red peak that represents the PIK3CA wild-type allele at nucleotide ments containing 60% tumor, providing an ideal position 31J4O0B (:to3p68 e1l9ectropherogram). Testing of nucIleSiScU aEc: id0 5e-0x9tr-1a3cted from sample for robust evaluation of somatic muta- the patient’s carcinosarcoma-biopsy sample (bottom electropherogram) tions. Total nucleic acids were extracted from the shows an additional prominent peak that indicates a c.3140A→G substitu- tion, encoding the PIK3CA His1047Arg mutation. tumor portion and then evaluated with the use of our SNaPshot clinical genotyping platform. A prominent peak was observed in the PIK3CA as- type II cancers. Alterations in KRAS, PTEN (en- say that evaluated nucleotide position 3140 (Fig. coding the phosphatase and tensin homologue), 4B). An A→G base substitution was identified, re- and CTNNB1 (encoding β-catenin) are more com- sulting in a change of histidine to arginine at 1832 n engl j med 368;19 nejm.org may 9, 2013 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on June 13, 2019. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. Frequency (%) case records of the massachusetts gener al hospital amino acid position 1047. This PIK3CA His1047Arg of 0 in patients with carcinosarcoma.36-38 Although mutation has been previously identified in uterine HER2-targeted therapy was initially promising, carcinosarcomas30 and is known to activate phos- clinical trials of single-agent therapy have been phoinositide-3-kinase (PI3K) activity, leading to disappointing.39 activation of the downstream AKT pathway.32,33 Given the presence of PTEN mutations in car- cinosarcoma, the phase 2 clinical trial of deforo- Discussion of M a nagemen t limus includes patients with carcinosarcoma; also, an increasing number of patients with PIK3CA Dr. Goodman: The patient’s extensive thrombus mutations have access to phase 1 and phase 2 was managed by vortex thrombectomy (en bloc clinical trials involving PI3K and AKT.40 Antian- aspiration of the thrombus), as well as infrarenal giogenic agents show promise in endometrial placement of an inferior vena cava stent and su- cancer, and trials of the new agent trebananib prarenal placement of an inferior vena cava filter, (formerly AMG 386) may enroll patients with with bilateral venoplasty. Anticoagulation was carcinosarcoma. We had one patient who did complicated by a subdural hematoma in the left exceptionally well on the histone deacetylase frontal, parietal, and temporal region, without inhibitor belinostat (PXD101), with carboplatin mass effect and with no neurologic sequelae. and paclitaxel.41 Carcinosarcomas have loss of A series of randomized, controlled trials has imprinting, which leads to biallelic overexpres- defined the standard of care for metastatic car- sion of insulin-like growth factor II (IGF-II) and cinosarcoma as either an inpatient regimen of concomitant overexpression of IGF-IR.42 Also, ifosfamide with paclitaxel or an outpatient regi- carcinosarcoma is a vivid example of epithelial- men of carboplatin with paclitaxel; these regi- to-mesenchymal transition; therefore, hedgehog mens are being compared in the randomized trial inhibitors, such as vismodegib and saridegib GOG-261 (NCT00954174).34 This patient wanted (IPI-926), are interesting treatment candidates. to prevent alopecia, so she was treated with three There were limited options for this patient cycles of carboplatin and pegylated liposomal- who did not have a response to platinum thera- encapsulated doxorubicin hydrochloride, a regi- py. Treatment with weekly paclitaxel was perhaps men shown to be effective in patients with ovar- her best chance of clinical benefit (although it ian cancer and less likely than carboplatin with was a small chance), and hospice or a clinical paclitaxel to cause alopecia.35 A fourth cycle, of trial were reasonable alternatives. She was not carboplatin alone, was given, owing to a short- eligible for a phase 2 clinical trial of E7080, an age of the doxorubicin. Despite therapy, the pa- oral antiangiogenic agent that targets vascular tient’s performance status deteriorated, the CA- endothelial growth factor receptor 2, because she 125 level rose to 968.4 U per milliliter (reference had had a “stroke” within the previous 6 months, range, <35.0), the alkaline phosphatase level was despite our petitioning that it was not a stroke but 925 U per liter (reference, 30 to 100), and a PET- an iatrogenic subdural hematoma. She signed a CT scan showed progression of disease in the consent form for SNaPshot analysis and 1 month retroperitoneum, liver, and spine and new metas- later returned to consider participating in a phase tases in the lungs. Worsening back pain devel- 1 clinical trial of an experimental PI3K inhibitor oped. Chemotherapy was discontinued, and the (NCT01219699). Unfortunately, her health had patient was treated with zoledronic acid and pal- declined precipitously; she was predominantly liative radiation to the lumbar spine with a total confined to bed and had jaundice and hypoten- of eight fractions of 3.5 Gy, totaling 28 Gy. sion (96/61 mm Hg). Results of liver-function tests Dr. Penson: Current therapeutic approaches for had worsened substantially, with the aspartate patients with carcinosarcoma are woefully inad- aminotransferase level rising from 60 to 251 U equate, and the emphasis should perhaps not be per liter (reference range, 9 to 32), and the bili- on phase 3 clinical trials but instead on expand- rubin level from 0.4 to 2.1 mg per deciliter (6.8 ing the understanding of the underlying biology to 35.9 μmol per liter) (reference range, 0.1 to of this disease, to identify new targets for thera- 1.0 mg per deciliter [1.7 to 17.1 μmol per liter]). peutic intervention. The hope for targeted therapy As a result, she was ineligible to enroll in the has so far been disappointing, with thalidomide, clinical trial of the PI3K inhibitor BYL719. She imatinib, and sorafenib all having a response rate elected to enroll in hospice, met the palliative care n engl j med 368;19 nejm.org may 9, 2013 1833 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on June 13, 2019. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. T h e n e w e ngl a nd j o u r na l o f m e dic i n e team, and died at home with her family 2 weeks than new agents and that the population of pa- later, 22 months after the initial diagnosis. tients with endometrial cancer is more obese and Dr. José Baselga (Medical Oncology): Carcino- older than the population of patients involved in sarcomas are unique in that they have abnor- breast cancer studies and thus is at greater risk malities in both the PI3K and the RAS pathways, for complications. Prescreening and selection of in contrast to other tumors, such as breast can- patients with relevant molecular abnormalities cer. This provides the opportunity to consider may further improve efficacy in these trials. experimental therapy involving a combination of inhibitors of both pathways. In assessing the A nat omic a l Di agnosis usefulness of mTOR (mammalian target of rapa- mycin) inhibitors in the clinical trials involving Malignant mixed müllerian tumor (carcinosar- patients with endometrial cancers, are you sure coma) of the uterus, with a PIK3CA mutation. that the dosing and schedule were optimal? This case was discussed at Cancer Center Grand Rounds. Dr. Penson: I agree that the newer targeted Dr. Penson reports receiving payment from Apotex for provid- agents show more promise. Older rapamycin- ing expert testimony in a case of Aventis Pharma S.A. v. Apotex Inc.; payment for serving on scientific advisory boards from Genen- based analogues at inadequate dose and subop- tech, AstraZeneca, Lifecore Biomedical, BioMarin Pharmaceuti- timal schedule have not been a fair trial of this cals, Clovis Oncology, and Seattle Genetics; and grant support class of agents for the treatment of endometrial through his institution from ImClone Systems, Endocyte, Astra-Zeneca, Eisai Pharmaceuticals, and Amgen. Dr. Borger reports cancer. However, the randomized phase 2 trial receiving consulting fees from Leerink Swann, Prous Science, GOG-248 was halted after only 22 participants and Bio-Reference Laboratories. Dr. Oliva reports providing ex- enrolled in the group assigned to receive tem- pert opinions in legal cases on behalf of patients or physicians. No other potential conflict of interest relevant to this article was sirolimus and alternating megestrol acetate and reported. tamoxifen, because of excess thromboembolic Disclosure forms provided by the authors are available with events and myocardial infarctions.43 The issues the full text of this article at NEJM.org.We thank Dr. Dror Michaelson for help with organizing the are that the older agents have more toxic effects conference. References 1. Doubilet PM. Diagnosis of abnormal ics of tumours of the breast and female Molecular markers and clinical behavior uterine bleeding with imaging. Meno- genital organs. Lyon, France: IARC Press; of uterine carcinosarcomas: focus on the pause 2011;18:421-4. 2003:245-9. epithelial tumor component. Mod Pathol 2. Benedet JL, Bender H, Jones H III, 7. Silverberg SG, Major FJ, Blessing JA, 2011;24:1368-79. Ngan HY, Pecorelli S. FIGO staging classi- et al. Carcinosarcoma (malignant mixed 13. 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