Anal cancer, of which fewer than 10,000 patients are diagnosed annually in the United States, is an uncommon type of cancer occurring in the tissue of the anus.1 However, rates of anal cancer are currently increasing at an annual rate of approximately 2% for unknown reasons.2

Anal cancers are typically characterized as squamous cell carcinomas (SCCs), although rarer forms of anal cancer — such as basal cell carcinoma, adenocarcinoma, and melanoma — also occur.3 Fewer clinical trials have been conducted with patients with basal cell carcinoma, and the National Comprehensive Cancer Network (NCCN) tends to treat anal basal cell carcinoma similarly to SCCs.3,4

Adenocarcinoma is often considered rectal instead of anal cancer, and appropriate pharmacologic treatment is discussed in the NCCN Guideline for Rectal Cancer and a separate article about colorectal cancer.3,5 Likewise, anal melanoma is typically treated similarly to melanoma present in the skin, and appropriate pharmacologic management can be found in the NCCN Guideline for Melanoma: Cutaneous and a separate article about melanoma.6

Abdominoperineal resection (APR) was historically the primary treatment for anal cancer, but disease recurrence and morbidity following surgery were generally high.7 Currently, the NCCN only recommends local resection for superficially invasive SCCs or when the cancer is an early-stage perianal carcinoma, is well differentiated, and does not involve the external or internal anal sphincter.4

For all other anal cancers, pharmacotherapy with or without concurrent external beam radiation therapy (EBRT) is the preferred treatment.4,8 Under current guidelines, localized anal cancer has a 5-year survival rate of 82%, although this prognosis drops to 36% for anal cancer with distant metastases.9 

This article will cover commonly used pharmacotherapies for anal cancer according to common anal cancer guidelines and their potential complications.4,10,11

MRI axial T2-weighted images demonstrating anal cancer
Figure. Magnetic resonance imaging of the anus, with axial T-2 weighted images demonstrating anal cancer. Credit: Getty Images

Chemotherapy for Anal Cancer

Chemotherapy is the recommended primary treatment for both local and metastatic anal cancer. Although there is currently no chemotherapy approved by the US Food and Drug Administration (FDA) to treat anal cancer, off-label chemotherapies have been commonly used to treat the disease since the 1970s.3 Exact treatment details, including concurrent radiation therapy, depend on the stage of disease.

Local Cancer (Stages I-III)

For patients with locoregional anal cancer, treatment typically involves combined fluorouracil (5-FU) and mitomycin plus radiation therapy.4,8,12-14 Both 5-FU and mitomycin inhibit DNA synthesis; 5-FU is converted into metabolites that block an enzyme responsible for DNA synthesis and thus the incorporation of new nucleotides into cellular DNA during cell division.15,16 However, capecitabine, an oral prodrug of 5-FU, was found to be equally effective when substituted for 5-FU in multiple studies.17-20 Cisplatin, which blocks normal DNA replication by forming interstrand and intrastrand cross-links, may also be used in place of mitomycin, although the NCCN categorizes this option as potentially less effective due to conflicting clinical trial results.4,21

Dosage and Administration

5-FU is administered via continuous intravenous (IV) infusion at a dosage of 1000 mg/m2/d on days 1 to 4 and days 29 to 32 during treatment.13,22 Concurrently, mitomycin is administered as an injection bolus either at a dose of 10 mg/m2 on days 1 and 29 or, alternatively, at a dose of 12 mg/m2 on only day 1. However, mitomycin dose reduction may be considered depending on white blood cell (WBC) and platelet counts23,24:

  • If nadir WBC count is between 1000/µL and 2400/µL or platelet count is between 50,000/µL and 85,000/µL, the second dose of mitomycin is reduced from 10 mg/m2 to 7.5 mg/m2.
  • If nadir WBC count is less than 1000/µL or platelet count is less than 50,000/µL, the second dose of mitomycin is reduced from 10 mg/m2 to 5 mg/m2.
  • If the WBC count is less than 2400/µL or the platelet count is less than 85,000/µL on day 28, further chemotherapy should be delayed by 1 week.

Capecitabine, when substituted for 5-FU, is administered orally at a dosage of 825 mg/m2 for 4 to 6 weeks, Monday through Friday, on each day that radiation therapy is also given.18,20

Cisplatin, when replacing mitomycin, is administered at a dose of 75 mg/m2 on the first day of treatment.25 Pretreatment hydration with IV fluids as well as pretreatment and post-treatment administration of antiemetics, such as ondansetron, are also recommended with cisplatin use.21

Metastatic Cancer (Stage IV)

The NCCN recommends platinum-based chemotherapy, specifically combined regimens of carboplatin and paclitaxel, as first-line agents for treating metastatic anal cancer.4 Other first-line treatments also exist, although they are widely considered to be either more toxic, less effective, or less researched than carboplatin and paclitaxel4,26:

  • 5-FU and cisplatin
  • 5-FU, leucovorin, and cisplatin (FOLFCIS)
  • 5-FU, leucovorin, and oxaliplatin (FOLFOX)
  • Modified docetaxel, cisplatin, and 5-FU (DCF)

To prevent recurrence of carcinomas at the primary site following metastasis, the NCCN also recommends chemotherapy with either 5-FU or capecitabine plus radiation therapy following first-line platinum-based chemotherapy.4

Data on the efficacy of chemotherapy for patients with metastatic anal cancer are scarce due to the rarity of the condition. Therefore, patients with metastatic anal cancer are encouraged to enter clinical trials over standard treatments.4,7

Carboplatin and Paclitaxel

Carboplatin is a platinum alkylating agent that disrupts DNA synthesis and is often given alongside paclitaxel, which inhibits cell replication.27,28 Carboplatin plus paclitaxel is often used to treat patients with locally recurrent or metastatic SCCs in the anal canal based on the results of a clinical trial that found the combination of carboplatin and paclitaxel to result in longer survival and less toxicity when compared with cisplatin plus 5-FU.26

Dosage and Administration

Pretreatment prophylaxis for nausea, vomiting, and allergic reactions prior to carboplatin and paclitaxel treatment is recommended to avoid hypersensitivity. Premedication may include dexamethasone, diphenhydramine, cimetidine, or ranitidine.28

Carboplatin is dosed by achieving a target area under the curve (AUC). For the most common carboplatin and paclitaxel regimens used in the treatment of metastatic anal cancer, the recommended AUC value is 5.26,29 The correct dosage of carboplatin can then be calculated using the patient’s glomerular filtration rate (GFR) and the Calvert formula30:

Dose (mg) = AUC (mg x min/mL) x (GFR + 25 [mL/min])

Two common regimens to treat metastatic anal cancer are:

  • Intravenous injections of carboplatin AUC 5 and paclitaxel 80 mg/m2 on day 1 of treatment every 21 days29
  • Intravenous injections of carboplatin AUC 5 on day 1 of treatment and paclitaxel 80 mg/m2 on days 1, 8, and 15 of treatment every 28 days26

5-FU and Cisplatin

Although carboplatin and paclitaxel are preferred by NCCN guidelines due to less toxicity, chemotherapy with 5-FU plus cisplatin is still shown to benefit some patients with metastatic anal carcinoma.26,31-33

Dosage and Administration

The NCCN guidelines recommend 2 alternative regimens for 5-FU plus cisplatin based on prior clinical trials4,32,34:

  • Intravenous injection of cisplatin 60 mg/m2 on day 1 and continuous IV infusion of 5-FU 1000 mg/m2/d on days 1 to 4, repeated every 3 weeks
  • Intravenous injection of cisplatin 75 mg/m2 on day 1 and continuous IV infusion of 5-FU 750 mg/m2/d on days 1 to 5, repeated every 4 weeks

FOLFCIS

FOLFCIS is a combination of leucovorin, 5-FU, and cisplatin that appears to be effective and safe as a first-line chemotherapeutic alternative to cisplatin and 5-FU for metastatic anal cancer.35 Leucovorin acts synergistically with 5-FU by enhancing the capacity of the metabolized form of 5-FU to block DNA synthesis.36

Dosage and Administration

During administration, cisplatin and leucovorin are administered on day 1 of treatment via IV over 30 minutes concurrently at the following doses35:

  • Cisplatin 40 mg/m2
  • Leucovorin 400 mg/m2

5-FU is then administered at 400 mg/mg2 as an IV bolus on day 1 followed by 1000 mg/m2/d on days 2 and 3. This entire regimen is repeated every 2 weeks until the end of treatment.35

FOLFOX

FOLFOX is similar to FOLFCIS except that cisplatin is replaced with oxaliplatin, an alkylating agent that inhibits DNA synthesis.37 Less data have been collected on the use of FOLFOX to treat anal cancer, although the regimen is commonly used off-label and was found in one case report to be safe when treating anal cancer.4,38

Dosage and Administration

FOLFOX is generally administered as follows4:

  • Oxaliplatin 85 mg/m2 IV on day 1
  • Leucovorin 400 mg/m2 IV on day 1
  • 5-FU 400 mg/mg2 as an IV bolus on day 1, followed by 1200 mg/m2/d on days 2 and 3

The above dosing regimen is repeated every 2 weeks.4

As oxaliplatin is considered one of the most neurotoxic chemotherapeutics, the NCCN guidelines recommend discontinuing this drug after 3 to 4 months of therapy, or sooner if unacceptable neurotoxicity occurs, while continuing the other agents.4 Anaphylactic reactions to oxaliplatin do occur, but they may be alleviated through administration of epinephrine, corticosteroids, or antihistamines.37

Modified DCF

DCF consists of docetaxel, cisplatin, and 5-FU, and it is used off-label to treat metastatic anal cancer.4 Docetaxel disrupts the microtubular network in cells, thus interfering with mitosis.39 Although multiple dosing schedules for DCF exist, one study found that standard DCF scheduling resulted in more serious adverse events.  Therefore, modified dosing is recommended for treatment of metastatic or recurrent anal SCCs.40

Dosage and Administration

Prior to treatment with docetaxel, patients should be premedicated with oral corticosteroids.39

Modified DCF is administered in the following manner4,40:

  • Docetaxel 40 mg/m2 IV on day 1
  • Cisplatin 40 mg/m2 IV on day 1
  • 5-FU 1200 mg/m2/d IV on days 1 to 2

This dosing regimen is then repeated every 2 weeks.4,40

Adjuvant Chemotherapy and Radiation Therapy

The NCCN guidelines recommend 5-FU or capecitabine with concurrent radiation as adjuvant therapy, assuming patients opt not to undergo APR and have not previously received radiation therapy to the groin.4

Dosage and Administration

When used concurrently with radiation therapy at the primary site of the tumor, administer 5-FU 225 mg/m2 via continuous IV drip over 24 hours on days 1 to 5 or days 1 to 7 for 5 weeks.41-43

Alternatively, administer capecitabine Monday through Friday twice daily on days 1 to 5, on the same days that radiation therapy occurs.44-46

Side Effects, Adverse Reactions, and Drug-Drug Interactions

Cytotoxic chemotherapy agents induce cell death of not only cancer cells but also healthy cells, which often results in significant side effects and the potential for adverse medical events. Thus, monitoring patients before, during, and after treatment is imperative.

The table below outlines common adverse reactions, drug-drug interactions, and considerations for special populations for chemotherapeutic agents used in the treatment of anal cancer.

Table 1. Side Effect Profiles for Chemotherapy for Anal Cancer

DrugCommon Adverse ReactionsDrug-Drug InteractionsSpecial Population Considerations
CapecitabineCardiotoxicity, diarrhea, dehydration, renal toxicity, serious skin toxicities, palmar-plantar erythrodysesthesia (hand-foot syndrome), myelosuppression, hyperbilirubinemiaVitamin K antagonists (eg, warfarin), allopurinol, leucovorin, phenytoin (via capecitabine-mediated inhibition of CYP2C9), other CYP2C9 substrates, nephrotoxic drugsDo not use in patients with DPYD gene variants due to increased risk for acute toxicities
Monitoring for adverse reactions required for patients with hepatic impairment 
Patients are advised not to become pregnant or breastfeed while undergoing treatment with capecitabine
CarboplatinHematologic toxicity, gastrointestinal toxicity, neurologic toxicity (especially peripheral sensory neuropathy), nephrotoxicity, hepatic toxicity, electrolyte changesNephrotoxic drugsPatients are advised not to become pregnant or breastfeed while undergoing treatment with carboplatin
CisplatinHypersensitivity reactions, ototoxicity, ocular toxicity, secondary leukemia, nephrotoxicity, peripheral neuropathy, nausea and vomiting, myelosuppressionNone indicatedAvoid in patients with hepatic impairment or monitor closely for adverse effects
Use with caution in geriatric patients
Patients are advised not to become pregnant or breastfeed while undergoing treatment with cisplatin
DocetaxelInfections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea and vomiting, diarrhea, mucositis, alopecia, skin reactions, myalgiaCYP3A4 substrates, inhibitors, or inducersDo not use on patients with hepatic impairment
Patients are advised not to become pregnant or breastfeed while undergoing treatment with docetaxel
Fluorouracil (5-FU)Cardiotoxicity, hyperammonemic encephalopathy, neurologic toxicity, diarrhea, palmar-plantar erythrodysesthesia, myelosuppression, mucositisVitamin K antagonists, CYP2C9 substrates Do not use in patients with DPYD gene variants due to increased risk for acute toxicities
Monitoring for adverse reactions required for patients with hepatic impairment 
Patients are advised not to become pregnant or breastfeed while undergoing treatment with 5-FU
LeucovorinStomatitis, diarrhea, nausea and vomitingTrimethoprim-sulfamethoxazoleNo or limited data exist on leucovorin’s effects on pregnant or breastfeeding patients
MitomycinBone marrow toxicity, skin and mucous membrane toxicity, renal toxicity, pulmonary toxicity, hemolytic uremic syndrome, cardiac toxicity, nausea and vomitingNone indicatedDo not use in patients with renal insufficiency or coagulation disorders
Patients are advised not to become pregnant or breastfeed while undergoing treatment with mitomycin
OxaliplatinPeripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea and vomiting, elevated transaminases and alkaline phosphatase, diarrhea, emesis, fatigue, stomatitisNone indicatedDose reduction required for patients with renal impairment
Patients are advised not to become pregnant or breastfeed while undergoing treatment with oxaliplatin
PaclitaxelHypersensitivity reactions, myelosuppression, alopecia, nausea and vomiting, diarrhea, infectionsSubstrates, inducers, or inhibitors of CYP2C8 and/or CPY3A4Monitoring for adverse reactions and potential dose reduction required for patients with hepatic impairment 
Use with caution in geriatric patients

From FDA-approved prescribing information.15,16,21,27,28,36,37,39,47

Immunotherapy for Anal Cancer

Immunotherapy stimulates the body’s immune system to attack cancerous cells. This new class of medications has shown promise for treating anal cancer. Multiple clinical trials are currently exploring the use of different immune checkpoint inhibitors as potential first-line or second-line treatments for metastatic anal cancer.4

Although no immunotherapy agent has yet obtained FDA approval for the treatment of anal cancer, the NCCN guidelines recommend nivolumab and pembrolizumab as second-line options for patients whose metastatic anal cancer has progressed during first-line platinum-based chemotherapy.4 Due to the rarity of microsatellite instability and mismatch repair in anal cancers, molecular testing is not suggested prior to treatment.4,48

The use of nivolumab or pembrolizumab is also recommended when patients opt to avoid APR following recurrent disease, although no published data support this practice.4

Immunotherapy is not currently recommended as a first-line treatment for metastatic anal cancer; however, clinical trials are currently investigating the efficacy of multiple checkpoint inhibitors, including nivolumab and retifanlimab.49,50

Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor that requires the presence of wild-type KRAS, is also being investigated as a treatment for anal cancer.51-53 Since most SCCs lack KRAS mutations, researchers consider cetuximab to be a promising direction for treatment of anal SSC.54,55

Nivolumab

Nivolumab is an antibody that blocks the interaction between the programmed death-1 (PD-1) receptors found on T cells and its ligands, programmed death ligand -1 (PD-L1) and PD-L2. By blocking this interaction, nivolumab prevents the inhibition of active T-cell tumor surveillance and thus results in anti-tumor activity.56 In a phase 2 trial, nivolumab was found to at least partially improve anal cancer patient outcomes in 24% of cases and is currently recommended for off-label use as a second-line option following chemotherapy.4,57

A large clinical trial is currently recruiting participants to determine if supplementing chemotherapy with nivolumab as a first-line treatment improves outcomes in patients with metastatic anal cancer.49

Dosage and Administration

The following regimens for nivolumab are currently recommended4,57:

  • 240 mg IV every 2 weeks
  • 3 mg/kg IV every 2 weeks
  • 480 mg IV every 4 weeks

Nivolumab should be discontinued if disease progression is noted despite treatment or unacceptable toxicity develops.4

Pembrolizumab

Pembrolizumab is another antibody that blocks the interaction between PD-1 receptors and their ligands to induce antitumor activity.58 Pembrolizumab is recommended for off-label use as a second-line therapy for metastatic anal cancer.4

Dosage and Administration

The following regimens for pembrolizumab are currently recommended4,59:

  • 200 mg IV every 3 weeks
  • 2 mg/kg IV every 3 weeks
  • 400 mg IV every 6 weeks

Pembrolizumab should be discontinued if disease progression is noted despite treatment or unacceptable toxicity develops.4

Side Effects, Adverse Reactions, and Drug-Drug Interactions

Immunotherapy is considered less toxic than conventional cytotoxic chemotherapy agents.60 Nonetheless, fatal immune-mediated adverse reactions are still possible. Thus, close monitoring of liver enzyme levels (aspartate aminotransferase and alanine transaminase), kidney function (creatinine levels), and thyroid function should be performed before and during treatment.58

The following table outlines common adverse reactions, drug-drug interactions, and considerations for special populations for immunotherapies currently recommended for treating anal cancer.

Table 2. Side Effect Profiles for Immunotherapy for Anal Cancer

DrugCommon Adverse ReactionsDrug-Drug InteractionsSpecial Population Considerations
NivolumabFatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal painNone indicated Patients are advised not to become pregnant or breastfeed while undergoing treatment with nivolumab
PembrolizumabFatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, abdominal painNone indicated Patients are advised not to become pregnant or breastfeed while undergoing treatment with pembrolizumab

From FDA-approved prescribing information.56,58

Monitoring Considerations During Systemic Anal Cancer Treatment

Pretreatment and Peritreatment Monitoring for Adverse Effects

Anal cancer is strongly associated with both human papillomavirus (HPV) and HIV infection. Therefore, HIV testing should be considered for all at-risk patients who do not already know their HIV status as HIV positivity leads to decreased antitumor immune response.4,10

In addition, all tissue specimens should be assessed for the presence of HPV. Infection of tumoral anal stratified squamous epithelial cells with HPV has been found to correlate with more positive treatment outcomes. In particular, histologic analysis of biopsy or surgical pathology samples for the p16 protein, which is a surrogate marker of HPV-infected cells, strongly predicts successful response to treatment.10

As most chemotherapeutic agents are known to cause fetal harm, premenopausal women should be screened for pregnancy prior to initiation of chemotherapy. If a patient is currently breastfeeding, lactation should be stopped and an alternate feeding method, such as bottle feeding with formula, chosen. Patients with renal or hepatic impairment may require additional monitoring or dose reductions during treatment.4,10

Based on the particular pharmacologic agents used for treatment, a baseline series of appropriate laboratory tests should be acquired.  Additional testing throughout treatment may be necessary to minimize toxicity and optimize drug dosage. These panels may include assessment of21,27,28:

  • Renal function,
  • Liver function, and
  • Complete blood count with differential.

Depending on the results of these examinations, dosage or scheduling may need to be altered.21,27,28

Premedication may also reduce the risk of adverse effects, including dehydration and nausea.21,27,28

Monitoring After Treatment

Following primary treatment of local anal cancer, surveillance and follow-up treatments are necessary. Typically, patients are re-evaluated between 8 to 12 weeks after completion of chemotherapy plus radiation therapy and determined to have remission of disease, persistent disease, or progressive disease. Patients with persistent but not progressive disease should undergo another follow-up evaluation in 4 weeks to determine if regression of the tumor has occurred or whether disease burden has progressed.4

The NCCN also recommends that patients with persistent anal cancer should be followed for up to 6 months with evaluation occurring in 3-month intervals following the end of treatment, as regression of the tumor is delayed in many patients.4,61 The goal of this delay is to avoid unnecessary and invasive APR.4

For patients with locally recurrent or persistent disease after 6 months, APR may be necessary to avoid recurrence. At this stage, EBRT is also strongly recommended for patients who have not previously received it as part of primary therapy.4

For patients in complete remission, the NCCN panel recommends a digital rectal examination and palpation every 3 to 6 months for 5 years to test for disease recurrence.4 However, as relapse after 3 years occurs in less than 1% of patients, extended surveillance using magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET)/CT is typically unnecessary.10

Anal cancer treatment, especially pelvic radiation, is associated with long-term toxicity. As a result, survivors of anal cancer should also be monitored for bowel, urinary, and sexual dysfunction.4

Cisplatin is also associated with an increased risk for leukemia.21

Considerations for Specific Populations

Patients With or At Risk for HPV or HIV

As individuals with HPV or HIV are at increased risk for anal cancer, gynecologic and rectal examinations as well as HIV testing are strongly suggested if a patient’s HPV and HIV status is unknown. All patients with HIV should also be tested for hepatitis B virus infection prior to chemotherapy to avoid hepatic toxicity.62 Although the NCCN does not recommend changes to treatment based on a patient’s HIV status alone, additional considerations may be necessary in the setting of HIV, including4:

  • Use of normal tissue-sparing radiation techniques
  • Consideration of nonmalignant causes for lymphadenopathy
  • More frequent post-treatment surveillance of the perirectal area using anoscopy

Patients living with HIV/AIDs often experience worse treatment outcomes due to additional burden from HIV-associated cancers (eg, Kaposi sarcoma), more frequent infections with atypical micro-organisms, and other causes. However, concomitant treatment with antiretroviral therapy may improve patient outcomes and promote the suppression of HIV viral load.4

HIV regimens often contain agents that are known inhibitors of CYP3A4, such as protease inhibitors. Inhibition of CYP3A4 is known to cause negative drug-drug interactions with certain chemotherapies, including docetaxel and paclitaxel, and caution should be exercised in the background of these known drug-drug interactions.62,39,28

Checkpoint inhibitors, such as nivolumab and pembrolizumab, are generally considered safe to use in people living with HIV/AIDs; however, an increased risk for Kaposi sarcoma-associated herpesvirus (KSHV) inflammatory cytokine syndrome is possible. Thus, clinicians should consider monitoring KSHV-positive patients more frequently for signs of inflammatory syndromes.62

Additional information about treating patients with HIV can be found in the NCCN Guidelines for Cancer in People Living with HIV.62

Men and Women of Childbearing Age

Most chemotherapy agents are contraindicated in women who are pregnant or considering pregnancy. In these patients, agents with known safety profiles in pregnancy should be selected or treatment delayed until after delivery. Alternatively, women may be counseled to consider conception only after treatment is over.4

Radiation therapy is typically recommended alongside many chemotherapeutic regimens when treating local anal cancer. Radiation therapy carries increased risk of infertility, early treatment-induced menopause, and changes to sexual function. Patients should be given information about banking sperm or eggs prior to treatment.4 In addition, patients should be informed about pelvic floor physical therapy and daily vaginal dilation to reduce the adverse effect of radiation exposure to sexual organs and the pelvic floor muscles.4

 

Geriatric Population

Geriatric patients often cannot tolerate mitomycin or other chemotherapeutic agents. The NCCN instead recommends a combination of weekly cisplatin and daily 5-FU on days of radiation therapy. Alternatively, patients may opt for capecitabine plus radiation therapy or radiation therapy without additional chemotherapy.4

Guidelines

Up-to-date guidelines for the management of patients with anal cancer are available, including:

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Author bio

Sierra Lear, PhD, earned a Bachelor of Science degree in chemical engineering and neuroscience from Tulane University and will graduate with a PhD in bioengineering from the University of California, Berkeley and the University of California, San Francisco in September 2023. She has spent a decade in the lab developing gene editing and other molecular tools to understand and treat different diseases.