The NCI-MATCH trial and precision medicine in gynecologic cancers

The Precision Medicine Initiative is a National Cancer Institute (NCI) driven interdisciplinary collaborative effort to test the feasibility of trials incorporating genomic profiling when choosing patient therapies. The goal of the initiative is to generate the scientific evidence needed to move the concept of precision medicine, or targeted therapy, into clinical practice. The rapid development and widespread availability of next generation sequencing provides access to information regarding an individual's tumor at various times during the course of their disease. Translating the aberrations specific to a patient's tumor into personalized treatment is the concept behind “basket” trials, and thus categorize patients' cancers based on the sequencing of the tumor, rather than the organ of origin. The NCI Molecular Analysis for Therapy Choice (MATCH) trial [NCT02465060] is a multi-site, collaborative effort between the NCI and several pharmaceutical companies that is beginning to clarify the significance of molecular alterations in tumors. This trial was designed to assign targeted treatment based on molecular alterations identified from a tumor biopsy obtained after study enrollment and determine the efficacy of this treatment. This review article will briefly discuss known genomic aberrations in gynecologic cancers, and then provide an overview of the NCI-MATCH trial with an update on accrual and recent interim analysis. We will also review current FDA-approved precision therapies for gynecologic malignancies, such as poly (ADP ribose) polymerase (PARP) inhibitors.     

Hyperthermia in gynecologic cancers

The opinion from most of the current data is that malignant tumors may be more heat sensitive than normal tissues. Hyperthermia has been tested in both randomized and non-randomized trials in gynecologic cancers, but has not found a place currently, as there is scarce data. As a consequence, adding this tool into the conventional methods of cervical cancer and ovarian cancer treatment has not been supported. Hyperthermia modifies the effects of not only ionizing radiation but also a number of chemotherapeutic agents. The use of hyperthermia in cervical cancer is of interest to the radiotherapist, not only because it sensitizes cells to the lethal effects of X-rays but even more because hypoxic cells which are most resistant to X-rays appear to be most sensitive to hyperthermia. Most of the data on the efficacy of intraperitoneal infusion with hyperthermia comes from experimental studies or some phase I/II investigations. Since intraperitoneal chemotherapy is potentiated by hyperthermia in areas which are at high risk for recurrence, further study maybe indicated. The current role for hyperthermia in ovarian cancer remains experimental. Additional trials to test the value of hyperthermia in patients treated with concurrent chemotherapy and radiation are imperative, and good news is expected from the ongoing studies.     

Plasma lipid profile in gynecologic cancers

BACKGROUND: Lipids are associated with cancer because they play a key role in the maintenance of cell integrity. We studied the relationship of plasma lipids with gynecologic cancer. METHODS: A total of 196 female individuals were included in the study. Of these 50 were normal subjects. The remaining were cancer patients: 80 breast cancer, 40 ovarian cancer and 26 patients with other gynecologic cancers. Plasma levels of triglycerides, total cholesterol, LDL-cholesterol and HDL-cholesterol were estimated by using spectrophotometer. RESULTS: In breast cancer patients there is moderate increase in the plasma levels of triglycerides (18%) and cholesterol (21%), and a high increase in LDL-cholesterol (43%), while there is a moderate decrease in HDL-cholesterol levels (30%) when compared with normal subjects. In ovarian cancer patients, there is a high decrease in the plasma levels of triglycerides (31%) and HDL-cholesterol (39%), while a moderate decrease in cholesterol (28%) and LDL-cholesterol levels (11%) when compared with normal subjects. In gynecologic cancers other than breast and ovarian cancer, there is a moderate decrease in plasma levels of the triglycerides (25%), cholesterol (21%), and HDL-cholesterol levels (27%), while a non-significant decrease in LDL-cholesterol (6.2%) when compared with normal subjects. CONCLUSIONS: Plasma lipid levels, except HDL-cholesterol, are raised in breast cancer and are decreased in other gynecologic cancers. HDL-cholesterol is decreased in all gynecologic cancers. As there is an alteration in the plasma lipid profile during gynecologic cancers, it may be helpful for diagnosis of the disease.     

Laparoscopic surgery for gynecologic cancers

In conclusion, laparoscopic techniques are useful for the evaluation and treatment of selected gynecologic malignancies and provide major benefits to patients. The benefits, however, can be expected only from gynecologic oncologists well-versed in advanced laparoscopic techniques. Results must be interpreted cautiously, depending on the laparoscopic expertise of the reporting authors. Numerous questions remain unanswered, particularly those associated with long-term recurrences and survival. The use of laparoscopic procedures for gynecologic malignancies must be considered investigational until adequate long-term survival data are available.     

Metronomic therapy for gynecologic cancers

Systemic administration of cytotoxic drugs is the primary treatment strategy for patients with advanced cancer. The effect of cytotoxic drugs is to disrupt the DNA of the cells, rendering them unable to replicate and finally killing them; therefore, the fundamental role of a wide range of treatment regimens is typically to induce lethal toxicity in the largest possible number of cancer cells. However, these cytotoxic drugs also damage the normal cells of the host, which limits the dose of the cytotoxic drug. Thus, cancer patients are usually treated at or near the maximum tolerated dose with the implicit intent of eradicating (curing) the tumor after balancing between efficacy in tumor killing and toxicity to the host. With significantly improving patient care, most efforts are focused on the corollary, "The higher the dose, the better." However, the concept that cancer could be considered as a chronic disease and might be treated like other chronic diseases to achieve a status called tumor dormancy is gaining popularity. In addition, there has been increasing interest in putting more effort into administering cytotoxic drugs on a more continuous basis, with a much shorter break period, or none at all, and generally lower doses of various cytotoxic drugs or combinations with other newer, targeted therapies, like anti-angiogenesis agents. This practice has come to be known as metronomic chemotherapy. There is still much to be learned in this field, especially with regard to optimization of the proper drugs, dose, schedule, and tumor type applications. This review will explore recent studies that have addressed the mechanism of metronomic chemotherapy in the management of various tumors, especially gynecologic cancers.     

Care of survivors of gynecologic cancers

The number of cancer survivors is increasing and most healthcare providers will manage patients who have completed therapy for malignancy at some point. The care of survivors of gynecologic malignancies may seem daunting in a busy general gynecology practice. This paper intends to review the literature and suggest management of these women for the general gynecologist.     

Impact of contraception on gynecologic cancers

In considering the appropriate contraceptive method for a particular woman, the potential effect of that method on her risk of developing cancer of the breast, cervix, endometrium, or ovary is crucial. Among the most closely studied of the risk factors for gynecologic neoplasm has been the potential role of contraceptives, especially oral contraceptives, intrauterine devices, and injectable progestins. Physicians need to consider the potential impact of these agents on the disease process, therapy for the disease, future fertility, and the health of the fetus. Although much of the epidemiologic data is inconsistent and difficult to interpret, most studies find no association between oral contraceptive use and increased risk of breast cancer, except possibly in younger women (< 45 years of age) with prolonged use. Oral contraceptive use may also protect against benign breast disease. Data concerning oral contraceptive use and cervical neoplasm are confounded by several interacting variables, the most important of which is that oral contraceptive users tend to have more Papanicolaou smears than nonusers. Some studies have indicated an increased risk of two- to fourfold after 10 years of use. Oral contraceptive use provides clear protection against endometrial and ovarian cancer, an effect that persists for years after discontinuation. Less data have been collected regarding the relationship between intrauterine devices and injectable hormonal preparations and various types of cancer. No evidence suggests that the intrauterine device predisposes to the development of preneoplastic conditions of the cervix, nor to endometrial or ovarian cancer. A reliable form of contraception is indicated in women with cancer of any kind that may require chemotherapy or radiation, because these treatments can have adverse effects on the fetus, especially if given during the first trimester. (Am J Obstet Gynecol 1993;168:1980-5.)     

Immunotherapy and chemotherapy of gynecologic cancers.

Recurrent cervical, ovarian, and breast cancers have been treated with immunochemotherapy. Optimum chemotherapeutic agents have been determined by direct and indirect methods of sensitivity determination. The Hellstr?m assay has been used for lymphocyte-tumor recognition and for cytotoxicity assays. Vaccines developed in this laboratory, consisting of autologous and allogeneic tumor-associated antigens, combined with BCG, have been used in immunotherapy. Objective tumor regression and notable clinical improvements have been observed. Forty-five advanced cases, including recurrent cancers of the cervix and ovary, along with sarcomas, breast malignancies, and melanomas, have been treated: 16 patients have died of their disease and 29 patients have survived for 6 months to 1 1/2 years. Some of these have shown either regression, total disappearance, or stabilization of their disease process. While the results of these preliminary studies are encouraging, the as yet unknown potential of this modality cannot be expected until it is applied earlier, at a time when residual tumor cells are minimal.     

Post-traumatic stress disorder in patients with gynecologic cancers

We present three cases of post-traumatic stress disorder (PTSD) that occurred in patients with gynecologic cancers. Case 1 and 2 had ovarian cancer and case 3 had endometrial cancer. The patients developed anxiety, difficulty in sleeping, and complaints of various discomforts after their diagnosis. On consulting with psychiatrists, PTSD was diagnosed based upon the DSM-IV classification. In cases 1 and 2, the symptoms worsened during the patients' primary treatment and interfered with their ability to continue the treatment. Psychiatric interventions were provided making it possible to complete their treatment. In case 3, the patient needed psychiatric intervention because of her psychological distress during her treatment. She was finally diagnosed as having PTSD. There are few reports regarding PTSD occurring in gynecologic cancer patients. However, attention should be given to the symptoms of these disorders so that patients may complete their standard therapies.     

Combination Adriamycin and radiation therapy in gynecologic cancers

Anthracyclic antibiotics, of which Adriamycin is representative, have the ability to bind to cellular DNA and thereby interfere with the X ray repair process. When radiation survival curves of tissue cultures were studied, increased cell-killing was noted in those cultures with Adriamycin over those without the drug. The mechanism by which this occurs may be related to a reduced rate of DNA strand break rejoining, as demonstrated by use of alkaline sucrose gradient techniques. A preliminary clinical Phase I study, in which patients with advanced gynecologic malignancy were treated by simultaneous Adriamycin and X radiation, suggests that combined therapy is well-tolerated, and that such combinations may prove useful in selected patients.     

Chemotherapy for gynecologic cancers occurring during pregnancy

Chemotherapy treatment of gynecologic malignancies during pregnancy should provide maternal benefit without undue fetal harm. We review the treatment regimens for gynecologic cancers occurring during pregnancy and the effects of chemotherapy on fetal development, parturition, and lactation. Women diagnosed with a gynecologic cancer during pregnancy require individualized treatment plans from a multidisciplinary team. TARGET AUDIENCE: Obstetricians & gynecologists, family physicians. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to specify the indications for chemotherapy in gynecologic cancers during pregnancy and postpartum periods, discuss the risks and benefits of chemotherapy for gynecologic cancer during pregnancy and postpartum periods. In addition, they should also be able to distinguish the mechanism of action of various chemotherapy agents to choose the best treatment options for patients and monitor for impacts of chemotherapy on fetal growth to determine the best treatment and management strategies.     

Multiple primary cancers associated with gynecologic malignancies

Seventeen multiple primary cancers including 16 double cancers and one triple cancer were found in 316 patients with gynecologic malignancies who were treated in our department from 1984 to 1988. All pathologic slides but one were reviewed, and cases with possible metastasis or recurrence were not included in this study. The incidence of multiple primary cancers in gynecologic malignancies was 5.4%. Multiple primary cancers were encountered in 4.4% of 205 cervical cancers (including carcinoma in situ), 15.2% of 33 endometrial cancers, and 8.6% of 58 ovarian cancers (including low potential malignancy), respectively. The most frequent sites of other cancers were seen in the large intestine and rectum (5/17), breast (4/17), and gynecologic organs (3/17). Higher incidences were seen in our study that in those in domestic literature. This is probably because detailed anamnesis and gastrointestinal series were obtained in most gynecologic malignancies (especially in endometrial or ovarian cancer).     

Primary gastrointestinal cancers presenting as gynecologic malignancies

OBJECTIVE: The goal of this study was to characterize presenting symptoms, prognostic factors, and treatment outcome in patients diagnosed with primary gastrointestinal (GI) cancers initially presumed to be of gynecologic origin. METHODS: A retrospective review of all admissions to the gynecologic oncology service at Saint Luke's Hospital in Kansas City, Missouri, was performed between 1993 and 2003. Twenty-six patients with primary GI cancers who presented with presumed gynecologic malignancies were identified. Clinical and pathologic features were reviewed, methods of diagnosis were recorded, and survival was analyzed by the Kaplan-Meier method. RESULTS: One percent of all gynecologic cancer referrals had a tumor of nongynecologic gastrointestinal origin. Seven subtypes of GI cancers were identified, most at stage 4 disease. Colon cancer was identified most commonly (26.9%). Abdominal pain was the most frequent symptom (57.6%), and an adnexal mass was diagnosed in the majority of patients (65.4%). Preoperative endoscopic evaluation provided a definitive diagnosis in only 3.8%. The median survival was 15 months with a 5-year survival of 35%. Ninety-six percent of patients had their GI tumor definitively diagnosed by exploratory laparotomy. Optimal cytoreduction provided a 7-month survival advantage. CONCLUSION: Most patients required a major surgical procedure to establish the primary diagnosis of gastrointestinal cancer. The cancers encountered were almost always at advanced stage disease and were referred to the gynecologic oncologist due to the presence of an adnexal mass and a failed preoperative work-up. Surgical management should include removal of the primary or recurrent GI tumor and cytoreduction of all bulky disease, including adnexal metastases.     

Descriptive epidemiology of gynecologic and breast cancers]

The epidemiology of gynecological and breast cancers are better known in France as a result of the mortality data provided by INSERM and the mortality data obtained from the French Tumor Register. Breast cancers are the most common form of cancer in women, accounting for about 30 p. cent of tumors (excluding skin cancers) followed by cancers of the uterine cervix, uterine body and the ovary. The change in incidence shows a definite reduction in the number of uterine cancers over the past 10 years, whereas the incidence of breast cancers is rising by 1 to 2 p. cent per year. Mortality due to breast cancer has risen steadily in France since 1950, particularly in higher age groups. At birth, the risk of developing a breast cancers is 7 p. cent, i.e. one woman in 14 will develop a breast cancer. The figures for cancers of the uterus and ovary are much lower. Survival curves for various types of cancer confirm the steady decline in survival for breast cancers, whereas for cancers of the cervix, uterine body and ovary, mortality rates stabilize after 5 years. The risk of a secondary cancer remains very high for breast tumors, and half the cases of a secondary tumor involve a contralateral breast tumor. In general, there is an increased risk of a secondary cancer after a primary gynecological tumor.     

Sentinel node procedures in gynecologic cancers: an overview

The aim of this study was to assess the value of sentinel lymph node procedures in gynecologic cancers. A systematic literature overview, using the PubMed database, was performed. In early stage vulvar, endometrial and cervical cancer, lymph node status is the most important prognostic factor. Lymphadenectomy, performed for adequate staging, is associated with high morbidity rates. Sentinel node procedures hold the promise of adequate staging with less treatment-related morbidity. Sentinel lymph node procedures in patients with early-stage vulvar cancer are associated with low recurrence rates, excellent survival, lower morbidity and shorter hospital stay compared to classical inguinal dissection. Therefore, these procedures should be the standard of care in early-stage unilateral vulvar cancer. Reports on sentinel lymph node procedures in endometrial and cervical cancer are ambiguous. The procedures in these cancers are reported in small studies only. Detection rates vary depending on the used injection sites and the used tracers. Bilateral detection rates are low and are not mentioned by default. Large controlled multi-institutional studies are necessary to evaluate the validity and the prognostic significance of the sentinel lymph node procedures in endometrial and cervical cancer.     

Positron emission tomography scanning in gynecologic and breast cancers

PURPOSE OF REVIEW: Positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose represents a noninvasive functional imaging modality that is based on metabolic characteristics of malignant tumors. The recent findings of this technique in breast cancer, cervical cancer, ovarian cancer, and other gynecologic malignancies are discussed. RECENT FINDINGS: In breast cancer, positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose is more accurate than conventional methods for the staging of distant metastases, enables early assessment of treatment response in patients undergoing primary chemotherapy. The diagnostic accuracy for axillary lymph node staging depends on the tumor load of the lymph nodes. The sensitivity of this technique in detecting primary breast cancer is limited in small breast lesions and invasive lobular cancer. In cervical cancer it is the most accurate noninvasive method for lymph node staging and it can accurately depict recurrent ovarian cancer in patients with elevated CA125 levels. False negative findings in well differentiated adenocarcinoma and borderline lesions as well as false positive findings in benign conditions limit the role of positron emission tomography scanning for the differential diagnosis of adnex tumors. SUMMARY: Positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose reveals unique information about tumor metabolism in gynecologic malignancies and breast cancer. This technique is complementary to morphological imaging for primary diagnosis, staging and re-staging. It may become the method of choice for the early assessment of treatment response in breast cancer and the detection of recurrent disease in ovarian cancer. This method, however, cannot replace invasive procedures if microscopic disease is of clinical relevance.