Research Into Talcum Powder–Ovarian Cancer Link Reveals ‘Troubling’ Differences Based on Study Designs

Research Into Talcum Powder–Ovarian Cancer Link Reveals ‘Troubling’ Differences Based on Study DesignsAn estimated 22,000 new cases of ovarian cancer are diagnosed in the United States each year, and mortality rates are high if the disease is not caught and treated early.

Members of the clinical community have attempted to identify modifiable risk factors. Some data suggested an association between genital talcum powder use and ovarian cancer risk. However, these data have not been consistent.

For this reason, Paolo Boffetta, MD, MPH, professor of medicine at Icahn School of Medicine at Mount Sinai and associate director for cancer prevention at Tisch Cancer Institute at Mount Sinai, and colleagues conducted a systemic review and meta-analysis of 27 studies that evaluated the association between genital talcum powder use and ovarian cancer risk.

Results showed ever use of genital talcum powder was associated with a summary relative risk of 1.22 (95% CI, 1.13-1.3). When researchers stratified the analysis according to study design, they observed an association between ovarian cancer risk and ever use of genital talcum powder in case–control studies (RR = 1.26; 95% CI, 1.17-1.35), but not in cohort studies (RR = 1.02; 95% CI, 0.85-1.2).

“[Although] some studies show an association between [talcum powder] use and ovarian cancer, the combined evidence falls short from demonstrating a causal link,” Boffetta said in a press release. “It would be premature to conclude that [talcum powder] use causes ovarian cancer.”

HemOnc Today spoke with Boffetta about the findings, their potential implications, and the questions that subsequent research will try to address.

Question: What prompted you and your colleagues to conduct this study?

Answer: I have been working for many years to research environmental exposures and the associated health risks. Part of this work has been in researching occupational and environmental exposures to dust and fibers, including asbestos and others. However, in recent years, attention has been brought to the genital use of talcum powder and the possibility of an association with ovarian cancer.

Before joining Mount Sinai, I was a researcher in France. where I was involved in several systematic reviews. One of these reviews focused on the carcinogenicity of talc — lung cancer risk among those who inhaled talc, and ovarian cancer risk among those who reported genital use of talc — so I have known about this issue for some time. A student of mine was particularly interested in ovarian cancer research and was aware of several studies that suggested an association between talcum powder use and ovarian cancer risk. We thought this would be a great study for her and a great chance to conduct a new systematic review on the topic.

Q: What did the overall findings suggest?

A: We found that not all the pieces of data fit together. Previous studies have shown an association between talcum powder use and risk for ovarian cancer. However, these studies are primarily case–control retrospective studies. We found that prospective studies did not show an association, but some of the retrospective studies did show an association. Overall, most of the studies we reviewed showed an association, but the differences observed between prospective and retrospective studies were troubling. In our opinion, this detracts from considering a causal association. Another main finding was that several of the studies showed different durations and frequencies of talcum powder use, and in general, there was no dose–response relationship. The results are not consistent. Therefore, our conclusion is that there is likely not a true biological association between talc use and cancer. In fact, there can be some bias with retrospective studies.

Q: What ingredient or ingredients might contribute to a possible association between talcum powder and ovarian cancer? 

A: Talcum is considered an inert mineral, but before 1970, some commercial versions of the powder were contaminated by fibers, including asbestos fibers. This type of contamination was eliminated after 1970. It is not clear which component of pure talcum, if any, may cause cancer.

Q: How would you describe the state of evidence a bout any potential association? 

A: In our study, we found a weak association between talcum powder use and ovarian cancer risk. However, this is just one piece of data, and other pieces of data suggest that the association might not be real. We need to do more research to see if this is a true biological association or if it reflects an issue arising from how studies have been conducted.

Q: How should physicians respond to patient concerns regarding talcum powder use and risk for ovarian cancer? 

A: First, I want to emphasize that we studied women who did not have ovarian cancer. We assessed the risk of talcum powder use as a factor in the potential development of ovarian cancer. We interpret our results more in a negative sense — that there does not seem to be a true link. Oncologists and other doctors should look at our data and look at other systematic reviews, and then they should decide whether it is wise to recommend against talcum powder use to prevent ovarian cancer in their patients. I do not think it is justified to worry about a possible risk of ovarian cancer from genital use of talcum powder.

Q: What might future research entail? 

A: We plan to obtain data on additional studies on talcum powder use and ovarian cancer risk that have not been published. We think there are more data to dig up, and this might better clarify the big picture. We also will research the potential mechanisms by which talc may cause ovarian cancer. We will look at molecular and genetic characteristics of ovarian cancer in women who reported talcum powder use and in women who did not report use. Again, if we do not find any associations, it will not support the hypothesis that genital talcum powder use increases the risk for ovarian cancer. – by Jennifer Southall

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Combination Yields ‘Promising’ Results for Recurrent, BRCA–Deficient Ovarian Cancer

Combination Yields ‘Promising’ Results for Recurrent, BRCA–Deficient Ovarian CancerResearchers at University of New Mexico Comprehensive Cancer Center are evaluating a novel treatment combination for women with recurrent ovarian cancer who have BRCA1 or BRCA2 gene mutations.

The phase 1 portion of the trial verified the safety of olaparib (Lynparza, AstraZeneca) — a PARP inhibitor that may exploit tumor DNA damage response pathway deficiencies to kill cancer cells — and tremelimumab, a CTLA-4 monoclonal antibody.

Enrollment for the phase 2 portion of the trial opened in May 2016.

Sarah F. Adams, MD, associate professor in the division of gynecologic oncology at University of New Mexico Comprehensive Cancer Center, spoke with HemOnc Today about the trial and why she thinks the combination approach will help improve outcomes in this patient population.

Question: Can you describe the rationale for this study?

Answer: The trial is based upon data we developed in our lab that initially tested the hypothesis that PARP inhibitors may sensitize BRCA–deficient ovarian cancer to immunotherapy, specifically immune checkpoint inhibitors. We have data — and other people also have produced data — that suggest BRCA–deficient ovarian cancer may be more visible to the immune system than BRCA wild-type ovarian cancers. In our lab, we showed that treating BRCA–deficient tumor cells with a PARP inhibitor further enhanced their immunogenicity, or their ability to be recognized and killed by T cells.

Q: Why do you think the combination approach may help improve outcomes?

A: We think that, if we combine this treatment with a PARP inhibitor, we can enhance tumor clearance and hopefully generate long-term results in patients. We have shown this in mouse models in the lab, and this trial is an opportunity to translate data to be able to benefit patients who are being treated at University of New Mexico.

Q: What have you found so far? 

A: We have observed promising results in some patients, which generated a lot of enthusiasm for us. However, it is too early to draw conclusions because we have not yet met our enrollment goals. We have submitted an embargoed abstract for the upcoming ASCO Annual Meeting.

Q: What do you hope you will find next? 

A: My hope is that we will find that the combination therapy not only reduces tumor burden, but also prolongs response compared with either drug alone. This is what we found with mouse models. The beauty of immunotherapy is that it can generate an immune response against the tumor, and it has the potential to create a memory response so that a person’s body rejects tumor recurrence.

Q: Once this trial is complete, what will future research entail?

A: This trial is designed to evaluate the response rate to this combination. We would like to expand the trial to evaluate the potential of this regimen to achieve long-term responses. Another area we are interested in expanding is to see whether the combination is effective for a larger cohort of women, because our trial is limited to women with BRCA mutations.

Q: Is there anything else that you would like to mention? 

A: The eligibility requirements for this trial are broad. There are no restrictions on the number of prior chemotherapy regimens a woman may have had before enrolling in this trial, and women who were previously treated with a PARP inhibitor also are eligible. All eligible patients who want to learn more about this trial may call University of New Mexico Comprehensive Cancer Center at (505) 272-4946 and ask for Sheri Westgate, RN, the nurse who is running the trial. – by Jennifer Southall

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Niraparib Approved for Ovarian Cancer Maintenance Tx

Niraparib Approved for Ovarian Cancer Maintenance TxNiraparib (Zejula, Tesaro) has been approved by the US Food and Drug Administration (FDA) for use in the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy.

Niraparib is a poly ADP-ribose polymerase (PARP) inhibitor, but unlike other drugs in this class, it is active both in patients with and those without BRCA mutations.

Another PARP inhibitor, olaparib (Lynparza, AstraZeneca), is restricted for use in patients with ovarian cancer who carry the BRCA mutation, which amounts to 15% to 20% of the patient population.

The approval is based on results from the phase 3 trial known as NOVA, which showed a significant improvement in progression-free survival (PFS) with niraparib compared to placebo.

These results were reported by Medscape Medical News last year when they were presented at the 2016 European Society for Medical Oncology (ESMO) Congress and were simultaneously published in the New England Journal of Medicine.

“This is a breakthrough for patients with ovarian cancer,” lead investigator Mansoor Mirza, MD, chief oncologist, Department of Oncology, Copenhagen University Hospital-Rigshospitalet, Denmark, said at the time.

“We have never seen such large benefits in PFS in recurrent ovarian cancer. Niraparib significantly improved all endpoints across a broad patient population, representing 70% of all ovarian cancer patients. These landmark results could change the way we treat this disease,” he added.

The trial was conducted in 553 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received at least two prior treatments of platinum-based chemotherapy and were in a complete or partial response to the most recent chemotherapy treatment. Within 8 weeks of their last therapy, patients were randomly allocated in a 2:1 ratio to receive either niraparib 300 mg orally daily or matched placebo.

This is also the dose that has been approved – niraparib 300 mg, taken once daily with or without food.

Patients in the NOVA trial were divided into two groups – those with germline BRCA mutation (n = 203) and those without (n = 350).

The results showed a significant improvement in PFS in both cohorts.

In the patients with a germline BRCA mutation, the estimated median PFS for those taking niraparib was 21 months compared with 5.5 months for those taking placebo (hazard ratio [HR] = 0.26; < .0001).

In patients without a mutation, the estimated median PFS for those taking niraparib was 9.3 months compared with 3.9 months for those taking placebo (HR = 0.45; < .0001).

“Significant Step Forward”

Discussing these results at the ESMO meeting, Sandro Pignata, MD, PhD, director, Instituto Nazionale Tumori, IRCCS Fondazione Pascale, Napoli, Italy, described the findings as a “significant step forward in the treatment of ovarian cancer.”

He said that the “main novelty” of the study in comparison with previous investigations with PARP inhibitors was that non-germline-mutation patients were included along with HRD-positive individuals.

For Dr Pignata, niraparib achieved “extraordinary results” in patients with BRCA mutations “that modified the clinical history of these patients,” and the patient subgroups experienced significant benefits. He said that overall, he feels these results will change the treatment of ovarian cancer and that we are ready to “move beyond” BRCA mutation for determining therapeutic choices.

Nevertheless, Dr Pignata asked, “Who are these patients who are responding to niraparib?” He noted that all patients were selected for being highly sensitive to platinum, “which is the main clinical parameter for selecting PARP inhibitors,” and questions remain as to why the different subgroups responded to treatment.

He added that it is important to note that a number of patients in the current study remained on treatment at 18 months, which has also been seen in trials of olaparib. “So, we have to concluded that there are many exceptional responders” to PARP inhibitors, he said. However, the across-the-board responses among subgroups means it is currently not possible to determine who will will have a long-term response.

Adverse Events

The FDA notes that niraparib’s safety was evaluated in 367 patients with platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancer in the NOVA trial. The most common adverse reactions occurring in at least 10% of patients receiving niraparib were thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain/distention, mucositis/stomatitis, diarrhea, dyspepsia, dry mouth, fatigue, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and hypertension. Myelodysplastic syndrome and/or acute myeloid leukemia occurred in 5 of 367 (1.4%) patients who received niraparib and in 2 of 179 (1.1%) patients who received placebo. Grade 3-4 hypertension occurred in 9% of niraparib-treated patients compared with 2% of patients who received placebo.

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No Link Between Methylation, Survival In Ovarian Cancer

No Link Between Methylation, Survival In Ovarian CancerUnlike mutation, methylation of homologous recombination DNA repair pathway genes was not linked to longer survival or platinum sensitivity in high-grade serous ovarian cancer, according to molecular and clinical analyses of 332 patients.

“Methylation may be more readily reversed than mutation, allowing more rapid development of platinum resistance and negating any impact on overall survival,” said Sarah Bernards, a second-year medical student at the University of Washington, Seattle, who presented the findings at the annual meeting of the Society of Gynecologic Oncology.

The homologous recombination (HR) DNA repair pathway is critical for repairing cross-linking and double-strand breaks, Ms. Bernards noted. Genes such as BRCA1, BRCA2, and RAD51C are important in this pathway, and inherited and sporadic mutations of these genes can lead to ovarian carcinoma. Importantly, ovarian cancers with HR gene mutations are more sensitive to platinum and radiation therapy and are associated with longer progression-free survival and overall survival compared with ovarian cancers without these mutations.

Methylation of the promoter regions of BRCA1 and RAD51C reduces expression of these genes and has been found to be associated with high-grade serous ovarian cancer, Ms. Bernards explained. One previous study found promoter methylations of BRCA1 and RAD51C in 11.5% and 3% of such tumors, respectively (Nature. 2011;474[7353]:609-15).

To further characterize HR gene methylations, Ms. Bernards and her associates used methylation-sensitive PCR to analyze ovarian carcinomas from patients who underwent primary debulking surgery and were enrolled in the University of Washington gynecologic oncology tissue bank. They also tested for damaging germline and somatic mutations in 16 HR DNA repair genes.

In all, 28% of cases had mutations in HR repair pathway genes, 7% had a BRCA1 methylation, and 3% had RAD51C methylation. BRCA1 and RAD51C methylation never overlapped with mutation (P = .001), and almost never overlapped with mutations in other HR DNA repair pathway genes, Ms. Bernards said.

Fully two-thirds of BRCA1 mutated cases were sensitive to chemotherapy, compared with 59% of BRCA1 methylated cases and 53% of wild-type BRCA1 cases (P = .03). Mutations of any HR DNA repair gene were associated with improved overall survival (hazard ratio, 0.7; 95% confidence interval, 0.5-0.9; P = .02), but methylation of RAD51C and BRCA1 was not (P = .3). Patients with HR gene mutations survived a median of 66 months after diagnosis, compared with 41 months for patients with RAD51C methylation and 43 months for patients with BRCA1 methylation.

Median age at diagnosis was 53 years for BRCA1 mutated cases (P less than .0001) and 55 years for BRCA1 methylated cases (P = .03), significantly lower than the 63-year median age for diagnosis of wild-type BRCA1 cases. High-grade histology characterized 71% of wild-type BRCA1 cases, compared with 82% of BRCA1 mutated cases (P = .001) and 91% of BRCA1 methylated cases (P = .05). Somatic TP53 mutations occurred in 67% of wild-type cases, 89% of mutated cases (P = .004), and 82% of methylated cases (P = .01).

To sum up, both methylation and mutation of BRCA1 were associated with younger age at diagnosis, high-grade histology, and TP53 mutations, but only BRCA1 mutation was tied to improved overall survival or platinum sensitivity, Ms. Bernards said.

The work was supported by a grant from the University of Washington School of Medicine Medical Student Research Training Program. Ms. Bernards conducted the work under Elizabeth Swisher, MD, a medical oncologist and head of the Swisher Lab at the University of Washington, Seattle. Ms. Bernards reported having no conflicts of interest.

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Maintenance Chemo After CR Fails to Extend Survival in Ovarian Cancer

Maintenance Chemo After CR Fails to Extend Survival in Ovarian CancerA long-term phase III randomized trial found that maintenance chemotherapy did not improve overall survival over surveillance among women with advanced ovarian/fallopian tube/peritoneal cancer who had a complete response (CR) to first-line therapy. Maintenance chemotherapy also increased toxicity in these patients.

Treating advanced-stage ovarian cancer with surgery and chemotherapy has a high CR rate, but following those responses there is a high probability of recurrent progressive disease, said Larry J. Copeland, MD, of Ohio State University, in a presentation delivered at the Society of Gynecologic Oncology (SGO) Annual Meeting in National Harbor, Maryland. Maintenance therapy has been proposed as a way to reduce that recurrence rate and thus extend survival.

The GOG 212 study began in 2005, and closed in 2014; Copeland presented its final survival analysis. A total of 1,157 patients with stage III-IV ovarian, tubal, or peritoneal cancer who achieved a clinical CR were randomized to surveillance, paclitaxel infusion every 28 days for 12 cycles, or CT-2103 (paclitaxel poliglumex [PP]) on the same schedule. Patients were followed for a median of 71 months; several patients in each group were ineligible, were not treated, or withdrew consent, leaving 1,051 patients for analysis.

The most common disease site was the ovaries, in approximately 85% of each group, followed by the peritoneum in about 11%, and the fallopian tube in about 4%. Most patients were stage III, with serous histology.

The median overall survival was no different between the groups, at 54.8 months with surveillance, 51.3 months with paclitaxel, and 60 months with PP. The hazard ratio (HR) for paclitaxel vs surveillance was 1.104 (97.5% CI, 0.884–1.38); for PP vs surveillance, it was 0.979 (97.5% CI, 0.781–1.23).

There was a slightly extended median progression-free survival with maintenance therapy. The median PFS was 13.4 months with surveillance, compared with 18.9 months with paclitaxel, and 16.3 months with PP. For paclitaxel compared to surveillance, the HR was 0.783 (95% CI, 0.666–0.921), and for PP vs surveillance it was 0.847 (95% CI, 0.721–0.0995).

Adverse events, in particular neurotoxic events, were increased with maintenance chemotherapy. Neurotoxicity of grade 1/2 occurred in 75.4% of PP patients, and in 79.4% of paclitaxel patients, compared with 54% of surveillance patients; grade 3/4 neurotoxicities occurred in 12.4%, 7.2%, and 1.9% of those groups, respectively. Other adverse events more common with maintenance therapy included allergic reactions, fatigue, alopecia, nausea, and constipation.

Quality-of-life measures showed similar results between the groups, with some poorer outcomes with the maintenance therapy.

Though it was not prospectively measured, there was some indication that patients with R0 disease did derive benefit from the maintenance therapy. Copeland said that question, along with the possibility that maintenance chemotherapy could induce chemoresistance in these patients, remain unanswered after this study.

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Immunotherapy Motolimod Fails to Improve Survival in Ovarian Cancer

Immunotherapy Motolimod Fails to Improve Survival in Ovarian CancerThe addition of the immune therapy motolimod to pegylated liposomal doxorubicin (PLD) failed to improve overall survival among women with recurrent epithelial ovarian carcinoma in a randomized phase II trial. There was a survival advantage, however, specifically in patients who experienced injection site reactions, which could help guide the use of this therapy.

Motolimod is a synthetic small molecule agonist of Toll-like receptor 8 (TLR8), delivered by subcutaneous injection. It functions by activating the innate immune system including monocytes, myeloid dendritic cells, and natural killer cells, thereby orchestrating an adaptive immune response. In the past, motolimod has been shown to enhance responses to anthracycline therapy, according to Bradley J. Monk, MD, of the University of Arizona College of Medicine in Phoenix, who presented results of the new trial at the Society of Gynecologic Oncology (SGO) Annual Meeting in National Harbor, Maryland.

The GOG-3003 trial enrolled 297 women with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma between 2012 and 2014; they were randomized to PLD plus motolimod or PLD plus placebo (149 patients in each group), administered until disease progression occurred. The median age in the study was 62.7 years, and most patients were white (93.6%). About half the patients (50.5%) had received one prior chemotherapy regimen, with slightly fewer (46.5%) receiving two prior lines, and 3% receiving three prior lines of chemotherapy.

The immune therapy failed to improve overall survival in the full cohort. The motolimod group had a median overall survival of 18.1 months, compared with 18.9 months with PLD and placebo, for a hazard ratio of 1.22 (P = .923). Similarly, the median progression-free survival was 4.8 months with motolimod and 5.2 months without it, for an HR of 1.21 (P = .943). The rates of response to therapy were also similar between the two groups, with an overall response rate of 20.9% with motolimod and 21.5% without it.

The researchers conducted a prespecified subgroup analysis based on whether or not an injection-site reaction (ISR) was present; 108 motolimod patients (73.5%) had an ISR, and 103 of those were within the landmark period of 56 days. The median overall survival among ISR-positive patients was 19.9 months, compared with 13.3 months in ISR-negative patients (P = .067).

A total of 42 PLD dose reductions or discontinuations were required in the motolimod group (28.6%), compared with 34 in the placebo group (23.1%); 74 reductions or discontinuations (50.3%) of motolimod were required, compared with 30.6% of placebo reductions or discontinuations. The same number of patients in each group had at least one serious treatment-emergent adverse event (40.8% in both); seven motolimod patients and six placebo patients had a serious adverse event resulting in death.

Translational analyses found no significant associations between overall survival or progression-free survival and an immune score based on tumor infiltrating lymphocytes, TLR8 single-nucleotide polymorphisms, or mutational status of BRCA and other DNA repair genes.

Though the addition of motolimod did not improve survival outcomes in this patient population, the finding that ISRs may be correlated to response could lead to better selection of patients for immunotherapies in the future, the researchers concluded.

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Patients With Ovarian Cancer Rank Nausea as Most Concerning Chemotherapy Side Effect

Patients With Ovarian Cancer Rank Nausea as Most Concerning Chemotherapy Side EffectPatients with newly diagnosed ovarian cancer rank nausea as the most concerning side effect associated with chemotherapy, according to a study presented at the 2017 Society of Gynecologic Oncology Annual Meeting.1

An important aspect of shared decision-making is patient preference of side effects associated with treatment. This analysis examined variations in preferences of patients with newly diagnosed ovarian cancer for different side effects associated with chemotherapy.

In this trial, patients with newly diagnosed ovarian cancer with a decision for route of administration for adjuvant chemotherapy were randomly assigned to participate in a computer-based decision aid (PCOA) or standard discussion. The PCOA included an explanation of major side effects and their severity levels including nausea, vomiting, neuropathy, fatigue, and abdominal pain. Patients then ranked 4 side effects with their 3 possible severity levels using a visual analog scale (VAS) of 1 to 100, with 100 representing the least preferred.

Quality of life was evaluated using the Functional Assessment of Cancer Therapy (FACT)-O-T01 for general, FACT-fatigue, and FACT/GOG-abdominal pain (AD) questionnaires.

Among 56 patients who had complete preference data, the mean age was 58, 93% were Caucasian, and 80% were considered to be in good health.

Mean preference ratings as measured using a VAS was 90 for severe nausea, 84 for pain, 74 for neuropathy, and 65 for fatigue. Mean quality of life scores were 66 for T01, 33 for FACT-fatigue, and 11 for FACT/GOG-AD.

The results of this study indicate that patients are most concerned about nausea compared with other side effects of chemotherapy evaluated in this analysis.

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