Premarket Evidence and Postmarketing Requirements for Real-Time Oncology Review Indication Approvals.

This cross-sectional study evaluates the use of the US Food and Drug Administration's Real-Time Oncology Review (RTOR) program in confirming the effectiveness of cancer drugs.

Biofilm-associated metabolism via ERG251 in Candida albicans.

Biofilm formation by the fungal pathogen Candida albicans is the basis for its ability to infect medical devices. The metabolic gene ERG251 has been identified as a target of biofilm transcriptional regulator Efg1, and here we report that ERG251 is required for biofilm formation but not conventional free-living planktonic growth. An erg251Δ/Δ mutation impairs biofilm formation in vitro and in an in vivo catheter infection model. In both in vitro and in vivo biofilm contexts, cell number is reduced and hyphal length is limited. To determine whether the mutant defect is in growth or some other aspect of biofilm development, we examined planktonic cell features in a biofilm-like environment, which was approximated with sealed unshaken cultures. Under those conditions, the erg251Δ/Δ mutation causes defects in growth and hyphal extension. Overexpression in the erg251Δ/Δ mutant of the paralog ERG25, which is normally expressed more weakly than ERG251, partially improves biofilm formation and biofilm hyphal content, as well as growth and hyphal extension in a biofilm-like environment. GC-MS analysis shows that the erg251Δ/Δ mutation causes a defect in ergosterol accumulation when cells are cultivated under biofilm-like conditions, but not under conventional planktonic conditions. Overexpression of ERG25 in the erg251Δ/Δ mutant causes some increase in ergosterol levels. Finally, the hypersensitivity of efg1Δ/Δ mutants to the ergosterol inhibitor fluconazole is reversed by ERG251 overexpression, arguing that reduced ERG251 expression contributes to this efg1Δ/Δ phenotype. Our results indicate that ERG251 is required for biofilm formation because its high expression levels are necessary for ergosterol synthesis in a biofilm-like environment.

Characterization of accelerated approval status, trial endpoints and results, and recommendations in guidelines for oncology drug treatments from the National Comprehensive Cancer Network: cross sectional study.

Objectives: To evaluate National Comprehensive Cancer Network (NCCN) guideline recommendations for oncology drug treatments that have been granted accelerated approval, and to determine whether recommendations are updated based on the results of confirmatory trials after approval and based on status updates from the US Food and Drug Administration (FDA). Design: Cross sectional study. Setting: US FDA and NCCN guidelines. Population: Oncology therapeutic indications (ie, specific oncological conditions for which the drug is recommended) that have been granted accelerated approval in 2009-18. Main outcome measures: NCCN guideline reporting of accelerated approval status and postapproval confirmatory trials, and guideline recommendation alignment with postapproval confirmatory trial results and FDA status updates. Results: 39 oncology drug treatments were granted accelerated approval for 62 oncological indications. Although all indications were recommended in NCCN guidelines, accelerated approval status was reported for 10 (16%) indications. At least one postapproval confirmatory trial was identified for all 62 indications, 33 (53%) of which confirmed benefit; among these indications, NCCN guidelines maintained the previous recommendation or strengthened the category of evidence for 27 (82%). Postapproval confirmatory trials failed to confirm benefit for 12 (19%) indications; among these indications, NCCN guidelines removed the previous recommendation or weakened the category of evidence for five (42%). NCCN guidelines reflected the FDA's decision to convert 30 (83%) of 36 indications from accelerated to traditional approval, of which 20 (67%) had guideline updates before the FDA's conversion decision. NCCN guidelines reflected the FDA's decision to withdraw seven (58%) of 12 indications from the market, of which four (57%) had guidelines updates before the FDA's withdrawal decision. Conclusions: NCCN guidelines always recommend drug treatments that have been granted accelerated approval for oncological indications, but do not provide information about their accelerated approval status, including surrogate endpoint use and status of postapproval confirmatory trials. NCCN guidelines consistently provide information on postapproval trial results confirming clinical benefit, but not on postapproval trials failing to confirm clinical benefit. NCCN guidelines more frequently update recommendation for indications converted to traditional approval than for those approvals that were withdrawn.

Regulatory features of Candida albicans hemin-induced filamentation.

Candida albicans is a prominent fungal pathogen that can infect the bloodstream and deep tissues. One key pathogenicity trait is the ability to transition between yeast and hyphal growth. Hyphae are critical for the formation of biofilms, which in turn enable device-associated infection. Among signals that drive hypha formation is the presence of hemin, an oxidized Fe(III)-containing heme derivative found in blood. In this study, we asked 4 questions. First, how uniform is the filamentation response to hemin among C. albicans strains? We tested 26 diverse isolates and found that the strength of a strain's filamentation response to hemin reflected its filamentation level in the absence of hemin. Second, does hemin induce biofilm formation? Hemin biofilm induction was evident in 5 out of 10 isolates tested, including most of the weaker biofilm formers tested. Third, what is the gene expression response to hemin? We compared RNA-seq data for type strain SC5314 grown in pH 5.5 minimal media with or without hemin. We also compared that response to SC5314 grown in pH 7.0 minimal media, where it undergoes well-studied pH-dependent filamentation. We found a common set of 72 genes with upregulated RNA levels in response to both signals, including many known hypha-associated genes. Surprisingly, overlap among those 72 genes with 2 recent consensus definitions of hypha-associated genes was limited to only 16 genes. Fourth, which regulators govern hemin-induced filamentation? A mutant survey indicated that the response depends upon filamentation regulators Efg1, Brg1, and Rim101, but not upon heme acquisition regulator Hap1 or its target genes HMX1, RBT5, PGA10, PGA7, and CSA2. These findings argue that hemin induces hypha formation independently of its utilization.

Commercial Versus Medicaid Insurance and Use of High-Priced Anticancer Treatments.

BACKGROUND: Because the markups on cancer drugs vary by payor, providers' financial incentive to use high-price drugs is differential according to each patient's insurance type. We evaluated the association between patient insurer (commercial vs Medicaid) and the use of high-priced cancer treatments. MATERIALS AND METHODS: We linked cancer registry, administrative claims, and demographic data for individuals diagnosed with cancer in North Carolina from 2004 to 2011, with either commercial or Medicaid insurance. We selected cancers with multiple FDA-approved, guideline-recommended chemotherapy options and large price differences between treatment options: advanced colorectal, lung, and head and neck cancer. The outcome was a receipt of a higher-priced option, and the exposure was insurer: commercial versus Medicaid. We estimated risk ratios (RRs) for the association between insurer and higher-priced treatment using log-binomial models with inverse probability of exposure weights. RESULTS: Of 812 patients, 209 (26%) had Medicaid. The unadjusted risk of receiving higher-priced treatment was 36% (215/603) for commercially insured and 27% (57/209) for Medicaid insured (RR: 1.31, 95% CI: 1.02-1.67). After adjustment for confounders the association was attenuated (RR: 1.15, 95% CI: 0.81-1.65). Exploratory subgroup analysis suggested that commercial insurance was associated with increased receipt of higher-priced treatment among patients treated by non-NCI-designated providers (RR: 1.53, 95% CI: 1.14-2.04). CONCLUSIONS: Individuals with Medicaid and commercial insurance received high-priced treatments in similar proportion, after accounting for differences in case mix. However, modification by provider characteristics suggests that insurance type may influence treatment selection for some patient groups. Further work is needed to determine the relationship between insurance status and newer, high-price drugs such as immune-oncology agents.

Costs to Medicare of Nonrecommended Bone-Modifying Agent Use for Castration-Sensitive Prostate Cancer.

PURPOSE: Bone-modifying agents (BMAs) do not prevent skeletal-related events among patients with castration-sensitive prostate cancer (CSPC), but many patients receive BMAs unnecessarily. The costs to Medicare from overuse have not been assessed. METHODS: We used linked SEER-Medicare data 2011-2015 to measure the frequency and number of doses of zoledronic acid (ZA) and denosumab received during CSPC (between diagnosis and initiation of metastatic, castration resistant prostate cancer therapy). We estimated excess BMA among patients who received BMA therapy for CSPC and did not have an indication for osteoporosis fracture prevention. We used the Medicare fee schedule for drug prices and peer-reviewed sources to estimate adverse event frequencies and costs. RESULTS: Median CSPC duration was 387 days (IQR, 253-573), during which time 42% of patients received ≥one dose of denosumab (mean doses, 7) and 18% received ≥one dose of ZA (mean doses, 7). Thirty-eight percent of those receiving denosumab and 47% of those receiving ZA had a history of osteoporosis, osteopenia, spine or hip fracture, or hypercalcemia. The estimated, annual excess BMA cost to Medicare was $44,105,041 in US dollars (USD), composed of $43,303,078 USD and $45,512 USD in drug costs for denosumab and ZA, respectively, and $682,865 USD and $75,585 USD in adverse event costs, respectively. In one-way sensitivity analysis, the estimate was most sensitive to denosumab dosing frequency (estimate range, $28,469,237 USD-$98,830,351 USD) and duration of CSPC (estimate range, $36,823,311 USD-$99,015,908 USD). CONCLUSION: BMA overuse in CSPC incurs substantial cost to Medicare, largely because of denosumab drug costs. Excess costs may be reduced by greater adherence to guideline-concordant BMA use.

Physician knowledge, practice patterns, and barriers encountered regarding guideline-concordant use of bone modifying agents for prostate cancer.

BACKGROUND: Guidelines recommend bone-modifying agents (BMAs) for patients with castrate-resistant prostate cancer (CRPC) and bone metastasis, but not for castrate-sensitive prostate cancer (CSPC). Physicians beliefs and practices regarding BMA therapy are poorly understood. METHODS: This was a qualitative interview study with embedded Likert-scale elements. Study participants were physicians who treat prostate cancer, located within an academic cancer center or an affiliated community-based network. Participants were asked about their experiences and practice patterns regarding BMA therapy. Participants used Likert-scale items to identify the most common barriers to guideline-concordant BMA use and the most effective potential interventions. Participants were subsequently asked to rank the three most common barriers and the three most effective interventions to reduce underuse (for CRPC) and overuse (for CSPC). RESULTS: Nineteen physicians were invited and 15 participated; one physician did not answer some questions as outside of their practice scope. All were aware of the recommendation for BMAs in CRPC. 14% (2/14) were unaware of the recommendation against BMA use for CSPC; an additional 29% (4/14) believed that BMA use could be appropriate for CSPC depending on the metastatic disease burden. 36% (5/14) were unaware of recommendations for screening and treatment of low bone mineral density. The most common barriers (occurring "often" or "sometimes") were obtaining dental clearance (11/15) and insufficient clinic time (6/15). The interventions identified as most effective to reduce underuse were dental navigation (11/15) and electronic medical record (EMR)-based guidance (9/15). The interventions identified as most effective to reduce overuse were peer-to-peer education (14/15) and EMR-based guidance (13/15). CONCLUSIONS: Awareness of guideline recommendations for screening and treatment of low bone mineral density and against BMA use for CSPC was good, but not complete. Dental navigation, peer-to-peer education, and EMR-based guidance were preferred intervention strategies to improve guideline-concordant use.

Pharmaceutical industry payments and delivery of non-recommended and low value cancer drugs: population based cohort study.

OBJECTIVE: To estimate the association between oncologists' receipt of payments from the pharmaceutical industry and delivery of non-recommended or low value interventions among their patients. DESIGN: Cohort study. SETTING: Fee-for-service Medicare claims. PARTICIPANTS: Medicare beneficiaries with a diagnosis of incident cancer (new occurrence of a cancer diagnosis code in proximity to claims for cancer treatment, and no such diagnosis codes during a ≥1 year washout period) during 2014-19, who met additional requirements identifying them as at risk for one of four non-recommended or low value interventions: denosumab for castration sensitive prostate cancer, granulocyte colony stimulating factors (GCSF) for patients at low risk for neutropenic fever, nab-paclitaxel for cancers with no evidence of superiority over paclitaxel, and a branded drug in settings where a generic or biosimilar version was available. MAIN OUTCOME MEASURES: Receipt of the non-recommended or low value drug for which the patient was at risk. The primary association of interest was the assigned oncologist's receipt of any general payments from the manufacturer of the corresponding non-recommended or low value drug (measured in Open Payments) within 365 days before the patient's index cancer date. The two modeling approaches used were general linear model controlling for patients' characteristics and calendar year, and general linear model with physician level indicator variables. RESULTS: Oncologists were in receipt of industry payments for 2962 of 9799 patients (30.2%) at risk for non-recommended denosumab (median $63), 76 747 of 271 485 patients (28.3%) at risk for GCSF (median $60); 18 491 of 86 394 patients (21.4%) at risk for nab-paclitaxel (median $89), and 4170 of 13 386 patients (31.2%) at risk for branded drugs (median $156). The unadjusted proportion of patients who received non-recommended denosumab was 31.4% for those whose oncologist had not received payment and 49.5% for those whose oncologist had (prevalence difference 18.0%); the corresponding values for GCSF were 26.6% v 32.1% (5.5%), for nab-paclitaxel were 7.3% v 15.1% (7.8%), and for branded drugs were 88.3% v 83.5% (-4.8%). Controlling for patients' characteristics and calendar year, payments from industry were associated with increased use of denosumab (17.5% (95% confidence interval 15.3% to 19.7%)), GCSF (5.8% (5.4% to 6.1%)), and nab-paclitaxel (7.6% (7.1% to 8.1%)), but lower use of branded drugs (-4.6% (-5.8% to -3.3%)). In physician level indicator models, payments from industry were associated with increased use of denosumab (7.4% (2.5% to 12.2%)) and nab-paclitaxel (1.7% (0.9% to 2.5%)), but not with GCSF (0.4% (-0.3% to 1.1%)) or branded drugs (1.2% (-6.0 to 8.5%)). CONCLUSIONS: Within some clinical scenarios, industry payments to physicians are associated with non-recommended and low value drugs. These findings raise quality of care concerns about the financial relationships between physicians and industry.

MicroMagnify: A Multiplexed Expansion Microscopy Method for Pathogens and Infected Tissues.

Super-resolution optical imaging tools are crucial in microbiology to understand the complex structures and behavior of microorganisms such as bacteria, fungi, and viruses. However, the capabilities of these tools, particularly when it comes to imaging pathogens and infected tissues, remain limited. MicroMagnify (µMagnify) is developed, a nanoscale multiplexed imaging method for pathogens and infected tissues that are derived from an expansion microscopy technique with a universal biomolecular anchor. The combination of heat denaturation and enzyme cocktails essential is found for robust cell wall digestion and expansion of microbial cells and infected tissues without distortion. µMagnify efficiently retains biomolecules suitable for high-plex fluorescence imaging with nanoscale precision. It demonstrates up to eightfold expansion with µMagnify on a broad range of pathogen-containing specimens, including bacterial and fungal biofilms, infected culture cells, fungus-infected mouse tone, and formalin-fixed paraffin-embedded human cornea infected by various pathogens. Additionally, an associated virtual reality tool is developed to facilitate the visualization and navigation of complex 3D images generated by this method in an immersive environment allowing collaborative exploration among researchers worldwide. µMagnify is a valuable imaging platform for studying how microbes interact with their host systems and enables the development of new diagnosis strategies against infectious diseases.

Candida albicans stimulates formation of a multi-receptor complex that mediates epithelial cell invasion during oropharyngeal infection.

Fungal invasion of the oral epithelium is central to the pathogenesis of oropharyngeal candidiasis (OPC). Candida albicans invades the oral epithelium by receptor-induced endocytosis but this process is incompletely understood. We found that C. albicans infection of oral epithelial cells induces c-Met to form a multi-protein complex with E-cadherin and the epidermal growth factor receptor (EGFR). E-cadherin is necessary for C. albicans to activate both c-Met and EGFR and to induce the endocytosis of C. albicans. Proteomics analysis revealed that c-Met interacts with C. albicans Hyr1, Als3 and Ssa1. Both Hyr1 and Als3 are required for C. albicans to stimulate c-Met and EGFR in oral epithelial cells in vitro and for full virulence during OPC in mice. Treating mice with small molecule inhibitors of c-Met and EGFR ameliorates OPC, demonstrating the potential therapeutic efficacy of blocking these host receptors for C. albicans.

Strain variation in gene expression impact of hyphal cyclin Hgc1 in Candida albicans.

Formation of hyphae is a key virulence trait of the fungal pathogen Candida albicans. Hypha morphogenesis depends upon the cyclin Hgc1, which acts together with cyclin-dependent protein kinase Cdc28 to phosphorylate effectors that drive polarized growth. Hgc1 has also been implicated in gene regulation through its effects on 2 transcription factors, Efg1 and Ume6. Here, we report RNA-sequencing (RNA-seq) analysis of 2 pairs of hgc1Δ/Δ mutants and their respective wild-type strains, which lie in 2 different genetic backgrounds. We find that hgc1Δ/Δ mutations alter expression of 271 genes in both genetic backgrounds and 266 of those genes respond consistently with regard to up- or down-regulation. Consistency is similar to what has been observed with efg1Δ/Δ mutations and greater than observed with nrg1Δ/Δ mutations in these 2 backgrounds. The gene expression response includes genes under Efg1 control, as expected from prior studies. Hgc1-responsive genes also include ergosterol biosynthetic genes and bud neck-related genes, which may reflect interactions between Hgc1 and additional transcription factors as well as effects of Hgc1 on cellular length-to-width ratios.

The cancer premium - explaining differences in prices for cancer vs non-cancer drugs with efficacy and epidemiological endpoints in the US, Germany, and Switzerland: a cross sectional study.

Background: High treatment prices of new cancer drugs are a global public health challenge to patients and healthcare systems. Policymakers in the US and Europe are debating reforms to drug pricing. The objective of this study was to assess whether drug efficacy or epidemiological characteristics (prevalence, incidence, mortality) explain the gap in treatment prices between cancer and non-cancer drugs in the US, Germany, and Switzerland. Methods: This cross-sectional study identified all new drugs approved in the US, Germany, and Switzerland between 2011 and 2020. Drug efficacy was extracted from pivotal trials, drug prices from public and commercial databases, and epidemiological characteristics from the Global Burden of Disease (GBD) 2019 study. We used regression models to explain drug prices with drug efficacy and epidemiological characteristics (prevalence, incidence, mortality). Findings: The cohort included 181 drugs, including 68 (37.5%) drugs approved for treatment of cancer. A significant negative correlation was found between incidence/prevalence and treatment prices, and a significant positive correlation was observed between mortality and treatment prices for both, cancer and non-cancer drugs. A significant association between relative drug efficacy and treatment prices of drugs was observed, however, less pronounced for cancer drugs. Our regression estimates indicated that after adjusting for efficacy and epidemiological characteristics, cancer drugs were on average approximately three times more expensive compared to non-cancer drugs in all three countries, indicating a cancer premium; i.e., treatment prices of cancer drugs were on average USD 74,412 (95% CI [62,810; 86,015]) more expensive in the US compared to non-cancer drugs, USD 37,770 (95% CI [26,175; 49,367]) more expensive in Germany, and USD 32,801 (95% CI [27,048; 38,555]) more expensive in Switzerland. Our model explained 72% of the variance in observed prices (R2). Interpretation: Drug pricing reforms should target the cancer premium to improve access of patients to cancer drugs as well as to achieve equity across the different therapeutic areas and sustainability in the health care systems. Funding: This study was funded by the Swiss National Science Foundation (SNSF, grant number PCEGP1_194607) and the Swiss Cancer Research Foundation (Krebsforschung Schweiz).

Glucose-enhanced oxidative stress resistance-A protective anticipatory response that enhances the fitness of Candida albicans during systemic infection.

Most microbes have developed responses that protect them against stresses relevant to their niches. Some that inhabit reasonably predictable environments have evolved anticipatory responses that protect against impending stresses that are likely to be encountered in their niches-termed "adaptive prediction". Unlike yeasts such as Saccharomyces cerevisiae, Kluyveromyces lactis and Yarrowia lipolytica and other pathogenic Candida species we examined, the major fungal pathogen of humans, Candida albicans, activates an oxidative stress response following exposure to physiological glucose levels before an oxidative stress is even encountered. Why? Using competition assays with isogenic barcoded strains, we show that "glucose-enhanced oxidative stress resistance" phenotype enhances the fitness of C. albicans during neutrophil attack and during systemic infection in mice. This anticipatory response is dependent on glucose signalling rather than glucose metabolism. Our analysis of C. albicans signalling mutants reveals that the phenotype is not dependent on the sugar receptor repressor pathway, but is modulated by the glucose repression pathway and down-regulated by the cyclic AMP-protein kinase A pathway. Changes in catalase or glutathione levels do not correlate with the phenotype, but resistance to hydrogen peroxide is dependent on glucose-enhanced trehalose accumulation. The data suggest that the evolution of this anticipatory response has involved the recruitment of conserved signalling pathways and downstream cellular responses, and that this phenotype protects C. albicans from innate immune killing, thereby promoting the fitness of C. albicans in host niches.

Candida albicans stimulates the formation of a multi-receptor complex that mediates epithelial cell invasion during oropharyngeal infection.

Fungal invasion of the oral epithelium is central to the pathogenesis of oropharyngeal candidiasis (OPC). Candida albicans invades the oral epithelium by receptor-induced endocytosis but this process is incompletely understood. We found that C. albicans infection of oral epithelial cells induces c-Met to form a multi-protein complex with E-cadherin and the epidermal growth factor receptor (EGFR). E-cadherin is necessary for C. albicans to activate both c-Met and EGFR and to induce the endocytosis of C. albicans . Proteomics analysis revealed that c-Met interacts with C. albicans Hyr1, Als3 and Ssa1. Both Hyr1 and Als3 were required for C. albicans stimulation of c-Met and EGFR in oral epithelial cells in vitro and for full virulence during OPC in mice. Treating mice with small molecule inhibitors of c-Met and EGFR ameliorated OPC, demonstrating the potential therapeutic efficacy of blocking these host receptors for C. albicans . Highlights: c-Met is an oral epithelial cell receptor for Candida albicans C. albicans infection causes c-Met and the epidermal growth factor receptor (EGFR) to form a complex with E-cadherin, which is required for c-Met and EGFR function C. albicans Hyr1 and Als3 interact with c-Met and EGFR, inducing oral epithelial cell endocytosis and virulence during oropharyngeal candidiasis Dual blockade of c-Met and EGFR ameliorates oropharyngeal candidiasis.

Functional Dichotomy for a Hyphal Repressor in Candida albicans.

Nrg1 is a repressor of hypha formation and hypha-associated gene expression in the fungal pathogen Candida albicans. It has been well studied in the genetic background of the type strain SC5314. Here, we tested Nrg1 function in four other diverse clinical isolates through an analysis of nrg1Δ/Δ mutants, with SC5314 included as a control. In three strains, nrg1Δ/Δ mutants unexpectedly produced aberrant hyphae under inducing conditions, as assayed by microscopic observation and endothelial cell damage. The nrg1Δ/Δ mutant of strain P57055 had the most severe defect. We examined gene expression features under hypha-inducing conditions by RNA-sequencing (RNA-Seq) for the SC5314 and P57055 backgrounds. The SC5314 nrg1Δ/Δ mutant expressed six hypha-associated genes at reduced levels compared with wild-type SC5314. The P57055 nrg1Δ/Δ mutant expressed 17 hypha-associated genes at reduced levels compared with wild-type P57055, including IRF1, RAS2, and ECE1. These findings indicate that Nrg1 has a positive role in hypha-associated gene expression and that this role is magnified in strain P57055. Remarkably, the same hypha-associated genes affected by the nrg1Δ/Δ mutation in strain P57055 were also naturally expressed at lower levels in wild-type P57055 than those in wild-type SC5314. Our results suggest that strain P57055 is defective in a pathway that acts in parallel with Nrg1 to upregulate the expression of several hypha-associated genes. IMPORTANCE Hypha formation is a central virulence trait of the fungal pathogen Candida albicans. Control of hypha formation has been studied in detail in the type strain but not in other diverse C. albicans clinical isolates. Here, we show that the hyphal repressor Nrg1 has an unexpected positive role in hypha formation and hypha-associated gene expression, as revealed by the sensitized P57055 strain background. Our findings indicate that reliance on a single type strain limits understanding of gene function and illustrate that strain diversity is a valuable resource for C. albicans molecular genetic analysis.

Hgc1 Independence of Biofilm Hyphae in Candida albicans.

Biofilm and hypha formation are central to virulence of the fungal pathogen Candida albicans. The G1 cyclin gene HGC1 is required for hypha formation under diverse in vitro and in vivo growth conditions. Hgc1 is required for disseminated infection and is a linchpin in the argument that hyphal morphogenesis itself is required for pathogenicity. We report here that HGC1 is dispensable for hypha formation during biofilm formation both in vitro, under strong inducing conditions, and in vivo, in a mouse oropharyngeal candidiasis model. These findings are validated with two or more C. albicans isolates. Systematic screening of overexpressed cyclin genes indicates that CCN1 and CLN3 can compensate partially for Hgc1 function during biofilm growth. This conclusion is also supported by the severity of the hgc1Δ/Δ ccn1Δ/Δ double mutant biofilm defect. Our results suggest that hypha formation in biofilm is accomplished by combined action of multiple cyclins, not solely by Hgc1. IMPORTANCE The HGC1 gene encodes a cyclin that is required for virulence of the fungal pathogen Candida albicans. It is required to produce the elongated hyphal filaments of free-living planktonic cells that are associated with virulence. Here, we show that HGC1 is not required to produce hyphae in the alternative growth form of a biofilm community. We observe Hgc1-independent hyphae in two infection-relevant situations, biofilm growth in vitro and biofilm-like oropharyngeal infection. Our analysis suggests that hypha formation in the biofilm state reflects combined action of multiple cyclins.