Category: Hem/Onc Updates

Artificial Intelligence Can Determine Appropriate Chemotherapy Regimen in Advanced Colorectal Cancer

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SUMMARY: Colorectal Cancer (CRC) is the third leading cause of cancer-related deaths in men and women in the United States. The American Cancer Society estimates that approximately 149,500 new cases of CRC will be diagnosed in the United States in 2021 and about 52,980 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the overall death rate has continued to drop, deaths from CRC among people younger than 55 years have increased 1% per year from 2008 to 2017, with 12% of CRC cases diagnosed in people under age 50. Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness.

First line treatment of metastatic CRC include Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine (FOLFOX or FOLFIRI), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. However numerous studies have failed to clearly establish that any of these combination regimens would be superior for any given patient based on clinical factors. In the TRIBE2 Phase III study, upfront FOLFOXIRI plus Bevacizumab and reintroduction after progression resulted in significant improvement in median Overall Survival (OS), compared to mFOLFOX6 plus Bevacizumab followed by FOLFIRI plus Bevacizumab, in patients with metastatic CRC. Majority of patients with mCRC receive FOLFOX-based first-line treatment, even though neuropathy almost always limits its use beyond 4 months. Oxaliplatin has also become a first line treatment option as part of FOLFOXIRI in mCRC, as part of FOLFIRINOX in advanced Pancreatic cancer and as a part of FOLFOX for other cancers such as GE Junction and Gastric cancer. A biomarker predicting the relative efficacy of these regimens is presently lacking. However, the availability of large, combined clinical and molecular datasets has enabled the development of a machine-learning approach.

Artificial intelligence (AI) refers to the intelligence demonstrable by man-made machines and can automatically extract required information from massive amounts of data, using mathematical algorithms, and is able to mimic human cognitive abilities, thereby providing rapid solutions to difficult healthcare challenges.

The authors conducted this study to determine a patients’ likelihood of benefit from first-line treatment with FOLFOX followed by FOLFIRI versus FOLFIRI followed by FOLFOX, by taking advantage of an advanced machine-learning approach, to identify a molecular signature (FOLFOXai), predictive of treatment benefit from FOLFOX chemotherapy, by analyzing a combined dataset of comprehensive molecular profiling results and clinical outcomes data.

The researchers leveraged AI algorithms and comprehensive molecular profiling data to develop a machine-learning approach, and identified a 67-gene molecular signature (FOLFOXai), predictive of clinical benefit from FOLFOX chemotherapy, in previously untreated patients with mCRC. The molecular signature included genes involved in mediating WNT signaling (BCL9 and CDX2), epithelial-to-mesenchymal transition (EMT; INHBA, PRRX1, PBX1, and YWHAE), chromatin remodeling (EP300, ARID1A, SMARC4, and NSD3), DNA repair (WRN and BRIP1), NOTCH signaling (MAML2), and cell-cycle regulation (CNTRL and CCNE1). They then validated the putative molecular signature from a large Real World Evidence (RWE) database, a subset of cases from the randomized controlled Phase III TRIBE2 study, as well as RWE data from patients with advanced Esophageal/Gastro Esophageal Junction cancers (EC/GEJ cancers) or Pancreatic Ductal AdenoCarcinoma (PDAC) who received first-line treatments with Oxaliplatin-containing regimens.

The researchers utilized Real World Evidence (RWE) outcomes dataset from the Caris Life Sciences Precision Oncology Alliance registry, and insurance claims data from more than 10,000 physicians. The training cohort or dataset included patients who had a diagnosis of mCRC, received treatment with FOLFOX-based combination therapy, completed at least one full cycle of therapy, and completed Next-Generation DNA analysis of at least one colorectal cancer sample using a 592-gene panel. Patients were excluded if they had prior chemotherapy, including adjuvant therapy.

Two separate RWE validation cohorts were also generated, and patients in these cohorts had a diagnosis of mCRC, received first-line treatment with FOLFOX/Bevacizumab (FOLFOX/Bevacizumab cohort) or FOLFIRI-based treatment (FOLFIRI cohort), completed at least one full cycle of therapy, completed Next-Generation DNA analysis of at least one CRC sample using a 592-gene panel, and switched to an Irinotecan-containing regimen (FOLFOX/bevacizumab cohort) or to FOLFOX (FOLFIRI cohort).

For algorithm training, a TTNT (Time To Next Treatment) of 270 days was chosen to define whether a patient benefitted from receiving first-line FOLFOX. Patients with TTNT of less than 270 days were referred to as having decreased benefit to FOLFOX and others were referred to as having increased benefit. Validation studies used Time To Next Treatment (TTNT), Progression Free Survival (PFS), and Overall Survival (OS) as the Primary endpoints.

A total of 105 patients with mCRC from the RWE dataset who had received first-line FOLFOX-based treatment and who had been profiled by Caris Life Sciences, were included in the training cohort. The first validation cohort included 412 patients (with RWE data on treatments and death dates) treated with FOLFOX/Bevacizumab and 55 patients who had received FOLFIRI as first-line treatments. Additional RWE datasets included 333 patients with advanced PDAC and EC/GEJC treated in first line with Oxaliplatin-containing regimens, and blinded retrospective-prospective analysis of samples from patients enrolled in the Phase III TRIBE2 study, with completed Next Generation Sequencing (NGS) analysis.

The researchers noted that
1) A 67-gene signature was cross-validated in a training cohort (N=105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit.
2) The gene signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI.
3) Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of overall survival in both Oxaliplatin-containing arms (FOLFOX HR=0.629; P=0.04 and FOLFOXIRI HR=0.483; P=0.02).
4) FOLFOXai was also predictive of benefit from Oxaliplatin-containing regimens in advanced Esophageal/Gastro Esophageal Junction cancers, as well as Pancreatic Ductal AdenoCarcinoma.

It was concluded from this analysis that application of FOLFOXai molecular signature could lead to improvements of treatment outcomes for patients with mCRC and other cancers, because patients predicted to have less benefit from Oxaliplatin-containing regimens might benefit from alternative regimens, thus providing critical guidance for the choice of first line therapy. The authors added that this is the first clinically validated, machine-learning powered molecular predictor of chemotherapy efficacy in these diseases, with immediate relevance for the initial therapeutic decision-making process.

Clinical Validation of a Machine-learning–derived Signature Predictive of Outcomes from First-line Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer. Abraham JP, Magee D, Cremolini C, et al. Clin Cancer Res 2021;27:1174-1183.

Genetic Testing in Older Women with Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

Genetic testing for cancer susceptibility with multigene testing panels is now becoming widely available and affordable. Identification of Pathogenic Variants in predisposition genes such as BRCA1 and BRCA2 among carriers has provided benefit through early intervention. There are 12 established breast cancer predisposition genes implicated among breast cancer cases, unselected for family history or young age at breast cancer diagnosis. Only loss-of-function through protein truncation and missense variants labeled as pathogenic, are classified as Pathogenic Variants-PV in the ClinVar database. They include ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53. Among these genes, BRCA1, BRCA2, and PALB2 are high risk genes, whereas the other genes are considered moderate risk. Identifying high risk genes in women with breast cancer is relevant both for prevention and treatment. Breast cancer prevention opportunities include contralateral prophylactic mastectomy or surveillance with MRI of the breast, prophylactic salpingo-oophorectomy for BRCA mutation carriers, avoidance of radiation in TP53 mutation carriers, and genetic testing for family members. PARP inhibitor LYNPARZA® (Olaparib) is indicated for the treatment of patients with deleterious or suspected deleterious germline BRCA1/2 mutated, HER2-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Younger age at diagnosis, strong family history of breast and/or ovarian cancer, Ashkenazi Jewish ancestry, or Triple Negative Breast Cancer (TNBC), are all associated with hereditary breast cancer and approximately 10% of these patients carry a Pathogenic Variant in a breast cancer predisposition gene.

According to the NCCN guidelines, hereditary cancer testing for women with breast cancer diagnosed at age greater than 65 years, without specific risk factors such as Ashkenazi Jewish ancestry or family history of cancer, has limited clinical utility as these women have less than 2.5% chance of having a Pathogenic Variant in a high risk gene. However, few studies have specifically evaluated breast cancer predisposition genes in women over age 65 years.

The authors conducted this study to determine the prevalence of Pathogenic Variants in established breast cancer predisposition genes, and to estimate remaining lifetime risks of breast cancer associated with Pathogenic Variants, among women over age 65 years in the general population. A total of 26,707 women over age 65 years from population-based studies (N=13,762, 51.5% with breast cancer and N=12,945, 48.5% age and study matched unaffected women controls) were tested for Pathogenic Variants in germline breast cancer predisposition gene. The researchers then assessed the frequencies of Pathogenic Variants and associations between Pathogenic Variants in each gene and breast cancer, and estimated the remaining lifetime breast cancer risks for non-Hispanic White women with Pathogenic Variants.

The researchers noted that the frequency of Pathogenic Variants in established breast cancer predisposition genes were identified in 3.18% of 13,762 women with breast cancer and 1.48% of the 12,945 age-matched unaffected controls. Pathogenic Variants in the high risk BRCA1, BRCA2, and PALB2 genes were found in 3.42% of women diagnosed with ER-negative breast cancer and 3.01% of women with Triple Negative Breast Cancer. The frequency of Pathogenic Variants in the high risk genes was low among women with no first degree relatives with breast cancer and ER-positive breast cancer. Pathogenic Variants in BRCA1, BRCA2, PALB2 and CHEK2 were associated with increased risks (Odds Ratio=2.9-4.0) of breast cancer. The remaining lifetime risk of breast cancer from age 66 to 85 years was more than 15% or more for those with Pathogenic Variants in BRCA1, BRCA2, and PALB2.

The authors concluded that based on this largest study to date of population-based US women over age 65 years, diagnosed with breast cancer, all women diagnosed with Triple Negative Breast Cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 Pathogenic Variants and perhaps with PALB2 and CHEK2 Pathogenic Variants should be considered for breast MRI screening, as they continue to be at an increased risk of breast cancer.

Risk of Late-Onset Breast Cancer in Genetically Predisposed Women. Boddicker NJ, Hu C, Weitzel JN, et al. J Clin Oncol 2021;39:3430-3440.

Initial Management of Noncastrate Prostate Cancer: ASCO Guideline Update

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 248,530 new cases of prostate cancer will be diagnosed in 2021 and 34,130 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second generation anti-androgen agents, which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis.

This recent ASCO guideline, updates all preceding ASCO guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer. This guideline was developed by a multidisciplinary expert panel and recommendations were made based on a systemic review of 4 clinical practice guidelines, 1 endorsement of a clinical practice guideline, 19 systematic reviews, 47 Phase III randomized controlled trials, 9 cohort studies, and 2 review papers.

Guideline Questions
CLINICAL QUESTION 1: What are the standard initial treatment options for metastatic noncastrate prostate cancer?
Recommendation 1: Docetaxel, Abiraterone, Enzalutamide, or Apalutamide, each when administered with Androgen Deprivation Therapy (ADT), represent four separate Standards of Care for noncastrate metastatic prostate cancer. The use of any of these agents in any particular combination or in any particular series cannot yet be recommended.
ADT Plus Docetaxel
Recommendation 1.1. For men with metastatic noncastrate prostate cancer with high-volume disease as defined per CHAARTED trial who are candidates for treatment with chemotherapy, the addition of Docetaxel to ADT should be offered.
Recommendation 1.2. For patients with low-volume metastatic disease as defined per CHAARTED trial who are candidates for chemotherapy, Docetaxel plus ADT should NOT be offered.
Recommendation 1.3. The recommended regimen of Docetaxel for men with metastatic noncastrate prostate cancer is six doses administered at 3-week intervals at 75 mg/m2 either alone (per CHAARTED trial) or with prednisolone.
ADT Plus Abiraterone
Recommendation 1.4. For men with high-risk de novo metastatic noncastrate prostate cancer, the addition of Abiraterone to ADT should be offered per LATITUDE trial.
Recommendation 1.5. For men with low-risk de novo metastatic noncastrate prostate cancer, ADT plus Abiraterone may be offered per STAMPEDE trial.
Recommendation 1.6. The recommended regimen for men with metastatic noncastrate prostate cancer is Abiraterone 1,000 mg with either prednisolone or prednisone 5 mg once daily until progressive disease is documented.
ADT Plus Enzalutamide
Recommendation 1.7. ADT plus Enzalutamide should be offered to men with metastatic noncastrate prostate cancer including both those with de novo metastatic disease and those who have received prior therapies, such as Radical Prostatectomy (RP) or RadioTherapy (RT) for localized disease. Enzalutamide plus ADT has demonstrated short-term survival benefits (PSA progression-free, clinical progression-free, and overall) when compared with ADT alone for men with metastatic noncastrate prostate cancer as a group per ENZAMET trial.
Recommendation 1.8. The recommended regimen for men with metastatic noncastrate prostate cancer is enzalutamide 160 mg per day with ADT.
ADT Plus Apalutamide
Recommendation 1.9. ADT plus Apalutamide should also be offered to men with metastatic noncastrate prostate cancer, including those with de novo metastatic disease or those who have received prior therapy, such as RP or RT for localized disease per TITAN trial.
Recommendation 1.95. The recommended regimen for men with metastatic noncastrate prostate cancer is Apalutamide 240 mg per day with ADT.
CLINICAL QUESTION 2: Are combination therapies such as combined androgen blockade (castration plus a nonsteroidal antiandrogen) better than castration alone, for men with noncastrate locally advanced nonmetastatic prostate cancer?
Recommendation 2.1. ADT plus Abiraterone and prednisolone should be considered for men with noncastrate locally advanced nonmetastatic prostate cancer, rather than castration monotherapy, because of the failure-free survival benefit per STAMPEDE trial. RT to the primary was mandated in STAMPEDE trial for patients with newly diagnosed node-negative, nonmetastatic disease and encouraged in patients with newly diagnosed node-positive, nonmetastatic disease. Failure-Free Survival (time to the earliest of biochemical failure, DP, or death) was significantly improved for patients with nonmetastatic disease treated with ADT plus Abiraterone and prednisolone compared with those treated with ADT alone, although ADT plus Abiraterone was administered for 2 or less years to men with nonmetastatic disease.
Recommendation 2.2. In resource-constrained settings where drugs such as Abiraterone may not be available, combined androgen blockade using ADT plus a first-generation antiandrogen, such as Flutamide, Nilutamide, or Bicalutamide, may be offered to men with locally advanced nonmetastatic prostate cancer, rather than castration monotherapy, based on recent meta-analyses.
CLINICAL QUESTION 3: Does early (immediate) Androgen Deprivation Therapy improve outcomes over deferred therapy for men with noncastrate locally advanced nonmetastatic disease?
Recommendation 3.1. Early (immediate) ADT may be offered to men who initially present with noncastrate locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo RT based on evidence in one meta-analysis of a modest, but statistically significant benefit in terms of both Overall Survival (OS) and Cancer-Specific Survival (CSS) among the larger population of men with locally advanced nonmetastatic disease.
CLINICAL QUESTION 4: Is Intermittent Androgen Deprivation Therapy better than continuous Androgen Deprivation Therapy for men with biochemically recurrent nonmetastatic disease?
Recommendation 4.1. Intermittent therapy may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer after RP and/or RT based on evidence in meta-analyses of the noninferiority of Intermittent Androgen Deprivation Therapy (IADT) when compared with Continuous Androgen Deprivation Therapy (CADT) with respect to OS. This is further supported by evidence from four meta-analyses testing superiority. Low-risk biochemical recurrence after RP is defined as a PSA doubling time more than 1 year and pathologic Gleason score less than 8. Low-risk biochemical recurrence after RT is defined as an interval to biochemical recurrence more than 18 months and clinical Gleason score less than 8. High-risk biochemical recurrence after RP is defined as a PSA doubling time less than 1 year or a pathologic Gleason score of 8-10. High-risk biochemical recurrence after RT is defined as an interval to biochemical recurrence less than 18 months or a clinical Gleason score of 8-10. Active surveillance may be offered to men with low-risk biochemically recurrent nonmetastatic prostate cancer.

Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update. Virgo KS, Rumble RB, de Wit R, et al. J Clin Oncol 2021;39:1274-1305.

Association of Age at Smoking Initiation and Cessation with Risk of Cancer Mortality

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SUMMARY: According to the American Cancer Society, tobacco use is responsible for about 1 in 5 deaths in the United States and is the leading preventable cause of death in the US. Smoking (cigarettes, cigars, and pipes) is responsible for about 20% of all cancers and about 30% of all cancer deaths in the US. Approximately 80% of lung cancers, as well as about 80% of all lung cancer deaths, are due to smoking, and lung cancer is the leading cause of cancer death in both men and women. Smoking also increases the risk for cancers of the Oral cavity, Oropharynx, Larynx, Esophagus, Stomach, Liver, Pancreas, Colon/Rectum, Kidney, Bladder, Cervix, as well as Acute Myeloid Leukemia.

Previous published studies have shown that individuals who start smoking at a younger age have greater mortality risk than those who start smoking later in life, and quitting to smoke especially at younger ages substantially reduces that mortality risk. However, the relevance of age at smoking initiation and cessation to cancer mortality, in contemporary US populations, particularly across the life course, is not clear.

The authors in this prospective cohort study investigated the association between age at smoking initiation and cessation, and cancer mortality, at ages 25 to 79 years. Data for this study was used from a cohort of 410,231 participants in the US National Health Interview Survey from 1997 to 2014, linked to the National Death Index, and follow up was continued through December 31, 2015. The mean patient age was 48 years and 56% were female. Self-reported current daily smokers were categorized by age at smoking initiation (less than 10 yrs, 10-14 yrs, 15-17 yrs, 18-20 yrs, and 21 or more years). Ex-smokers were categorized by age at quitting (15-34 yrs, 35-44 yrs, 45-54 yrs, or 55-64 years). Current nondaily smokers (4% of cohort) and ex-smokers who quit at ages younger than 15 years or 65 years and older (1% of cohort) were excluded from the analysis. Cancer mortality rate ratios were adjusted for age at risk, sex, race and ethnicity, education, region and alcohol consumption.

There were 10,014 cancer deaths at ages 25 to 79 years during 3.7 million person-years of follow-up (mean=10 plus or minus 5 years). Compared with never smokers, the overall cancer mortality rate ratio associated with current smoking was 3.00, suggesting that current smoking was associated with three times the cancer mortality rate of never smoking.

For individuals who started smoking at age younger than 10 yrs, the cancer mortality rate ratio was 4.01, 3.57 for those ages 10-14 yrs, 3.15 for those ages 15-17 yrs, 2.86 for those ages 18-20 yrs and 2.44 for those ages 21 yrs and older. The researchers pointed out that if these excesses were interpreted as largely causal, smoking would account for 75% of cancer deaths among those starting before age 10 yrs and 59% among those starting at age 21 yrs and older. Those who quit smoking at ages 15-34 yrs, 35-44 yrs, 45-54 yrs, and 55-64 yrs avoided an estimated 100%, 89%, 78%, and 56% of the excess cancer mortality risk associated with continued smoking, respectively.

The authors concluded that in this contemporary US population, current smoking was associated with 3 times the cancer mortality rate of never smoking, and the researchers added that the findings from this study underscore that starting to smoke at any age is extremely hazardous. However, smokers who quit especially at younger ages can avoid most of the cancer mortality risk associated with continued smoking.

Association of Smoking Initiation and Cessation Across the Life Course and Cancer Mortality: Prospective Study of 410 000 US Adults. Thomson B, Emberson J, Lacey B, et al. JAMA Oncol. Published online October 21, 2021. doi:10.1001/jamaoncol.2021.4949

KEYTRUDA® for BCG-Unresponsive High-Risk Non-Muscle Invasive Bladder Cancer

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SUMMARY: The American Cancer Society estimates that for 2021, about 83,730 new cases of bladder cancer will be diagnosed in the US and about 17,200 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but is less common in women and the average age at the time of diagnosis is 73. With regards to racial predisposition, Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Approximately 50% of all bladder cancers are non-invasive or in situ cancers. Patients with high-risk, Non-Muscle Invasive Bladder Cancer that has become unresponsive to BCG (Bacillus Calmette-Guerin) treatment, are often given the treatment option of radical cystectomy, which includes removing the entire urinary bladder and a prostatectomy for men or total hysterectomy in women. While highly curative, this surgical procedure carries substantial risk for morbidity and mortality, and can negatively impact patient’s quality of life. Further, a significant proportion of patients are medically ineligible for a radical cystectomy, and even if eligible, refuse surgery and opt for other less effective treatments, which could compromise outcomes.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. KEYTRUDA® is presently approved by the FDA for the treatment of patients with locally advanced or metastatic Urothelial carcinoma who are not eligible for Cisplatin-containing chemotherapy or for those with disease progression during or following platinum-containing chemotherapy, based on its durable antitumor activity in this patient group. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting that KEYTRUDA® may be of benefit in this group of patients. The FDA in 2020, approved KEYTRUDA® for the treatment of patients with BCG-unresponsive, high-risk, Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma In Situ (CIS) with or without papillary tumors, who are ineligible for or have elected not to undergo cystectomy, based on the KEYNOTE-057 study.

KEYNOTE-057 study is an international, multicenter, single arm, open-label, Phase II trial that enrolled 101 eligible patients with high-risk NMIBC, who had BCG-unresponsive CIS with or without papillary tumors. BCG-unresponsive high-risk Non-Muscle Invasive Bladder Cancer was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Eligible patients had received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy. All patients had undergone TransUrethral Resection of Bladder Tumor (TURBT) to remove resectable disease. Patients with residual Carcinoma In Situ, not amenable to complete resection were permitted. Patients received KEYTRUDA® 200 mg IV every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. The efficacy analysis included 96 patients, as 5 patients did not meet the FDA BCG-unresponsive criteria.

The median age was 73 years and the median number of prior BCG instillations was 12. More than half of patients (56.9%) had a PD-L1 Combined Positive Score (CPS) of less than 10, and most patients in this analysis had refused prior cystectomy. The Primary end point was Complete Response Rate (CRR-absence of high-risk non-muscle invasive bladder cancer or progressive disease) as defined by negative results for cystoscopy with TURBT/biopsies as applicable, urine cytology, and CT Urography imaging, approximately 3 months after the first dose of KEYTRUDA®. Secondary end points included Duration of Response and Safety.

At a median follow up of 36.4 months, the Complete Response Rate at 3 months was 41% and the median Duration of Response was 16.2 months. Forty-six percent (46%) of responding patients experienced a Complete Response lasting 12 months or more. The Complete Response Rate was consistent with the primary analysis across protocol-prespecified subgroups, including PD-L1 expression status. The most frequent adverse reactions were fatigue, diarrhea, rash, pruritis, arthralgia, musculoskeletal pain, peripheral edema and hypothyroidism.

It was concluded that with extended follow up, KEYTRUDA® monotherapy continued to show durable and clinically meaningful antitumor activity in patients with high risk BCG-unresponsive, non-muscle invasive bladder cancer, who declined or were ineligible for radical cystectomy. The authors added that KEYTRUDA® should be considered a clinically active non-surgical treatment option in this difficult-to-treat population.

Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Balar AV, Kamat AM, Kulkarni GS, et al. The Lancet Oncology. 2021;22:919-930.

FDA Approves SCEMBLIX® for Chronic Myeloid Leukemia

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SUMMARY: The FDA on October 29, 2021, granted accelerated approval to SCEMBLIX® (Asciminib), for patients with Philadelphia chromosome-positive Chronic Myeloid Leukemia (Ph-positive CML) in Chronic Phase, previously treated with two or more Tyrosine Kinase Inhibitors (TKIs), and approved SCEMBLIX® for adult patients with Ph-positive CML in Chronic Phase with the T315I mutation.

The American Cancer Society estimates that about 9,110 new CML cases will be diagnosed in the United States in 2021 and about 1,220 patients will die of the disease. Chronic Myeloid Leukemia (CML) constitutes about 15% of all new cases of leukemia and the average age at diagnosis of CML is around 64 years. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells.

The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States share the same therapeutic target, which is the ATP-binding site of BCR-ABL1 kinase. Close to 50% of clinical resistance is associated with the acquisition of mutations in this region of the kinase, resulting in conformational changes that render TKIs inactive. Therefore resistance to one of the TKIs, will likely result in resistance to the others as well. Further, the “gatekeeper” T315I mutation, which has been reported in 20% of patients with mutations, confers resistance to all clinically available TKIs except ICLUSIG® (Ponatinib).

SCEMBLIX® is a novel, first-in-class, potent and specific, oral BCR-ABL1 inhibitor that does not bind to the ATP-binding site of the kinase. Instead, it specifically targets the ABL1 myristoyl pocket, also known as a STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, with activity against native unmutated BCR-ABL1, and all clinically observed ATP-site mutants, including T315I. In a Phase I study, SCEMBLIX® was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ICLUSIG® had failed, and those with a T315I mutation.

The present FDA approval was based on data from the Phase III ASCEMBL trial which evaluated this agent in patients with Ph-positive CML who previously received 2 or more TKIs, and the Phase I CABL001X2101 trial, which evaluated its use in patients with Ph-positive CML in Chronic Phase harboring a T315I mutation.

ASCEMBL is a multicenter, randomized, active-controlled, open-label, Phase III trial, which evaluated SCEMBLIX® in patients with Ph-positive CML in Chronic Phase, previously treated with two or more TKIs. In this study, a total of 233 patients were randomized (2:1) to receive either SCEMBLIX® 40 mg twice daily (N=157) or BOSULIF® (Bosutinib) 500 mg once daily (N=76). Patients were stratified by Major Cytogenetic Response (MCyR; Ph-positive metaphases 35% or less at baseline). Patients intolerant of their most recent TKI were eligible if they had BCR-ABL1 International Scale more than 0.1% at screening. Treatment was continued until unacceptable toxicity or treatment failure occurred. The median patient age was 52 years and 48% of patients had received 2 prior lines of treatment, 31% received 3 prior lines of therapy. The Primary endpoint was Major Molecular Response (MMR) rate at 24 wks.

In this study, the MMR rate was 25.5% in patients treated with SCEMBLIX® compared with 13.2% in those receiving BOSULIF®, meeting the primary objective of this study (P=0.029). At a median follow up of 20 months, the median duration of MMR has not yet been reached. Among those pts who achieved MMR, the median time to MMR was 12.7 weeks among those who achieved MMR with SCEMBLIX®, and 14.3 weeks with BOSULIF®. At 24 wks, more patients on SCEMBLIX® (19.7%)] achieved Deep Molecular Response (MR4 and MR4.5), compared with 6.6% with BOSULIF®. The Complete Cytogenetic Response rate at 24 weeks was 40.8% with SCEMBLIX® compared with 24.2% for BOSULIF®. Additionally, preplanned subgroup analysis showed that the MMR rate at 24 weeks was superior with SCEMBLIX® compared to BOSULIF® across most major demographic and prognostic subgroups, including among patients who received 3 or more prior TKIs, in those who discontinued the prior TKI due to treatment failure, and regardless of baseline Cytogenetic Response.

CABL001X2101 is a multicenter, open-label clinical trial, in which the efficacy of SCEMBLIX® was evaluated in patients with Ph-positive CML in Chronic Phase, with the T315I mutation. In this study, 45 patients with the T315I mutation received SCEMBLIX® 200 mg twice daily and treatment was continued until unacceptable toxicity or treatment failure. The main efficacy outcome measure was MMR.

MMR was achieved by 24 weeks in 42% of the patients, and 49% of the patients achieved MMR by 96 weeks. The median duration of treatment was 108 weeks.

The most common adverse reactions included upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, diarrhea, and cytopenias. Patients also were noted to have increased triglycerides, increased creatine kinase, alanine aminotransferase, lipase, and amylase.

It can be concluded from these two studies that SCEMBLIX®, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy, compared with BOSULIF®, among patients with Chronic Phase CML previously treated with two or more TKIs. SCEMBLIX® is also a new treatment option for patients with Ph-positive CML in Chronic Phase, harboring a T315I mutation.

A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After ≥2 Prior TKIs. Rea D, Mauro MJ, Boquimpani C, et al. Blood. 2021 Aug 18;blood.2020009984. doi: 10.1182/blood.2020009984. Online ahead of print.

Randomized Controlled Trial of Central Venous Access Devices for the Delivery of Systemic Anticancer Therapy

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SUMMARY: The American Cancer Society estimates that in 2021, there will be an estimated 1.9 million new cancer cases diagnosed and 608,570 cancer deaths in the United States. Currently, more than 80% of all cancer care is delivered in outpatient oncology practice settings and tunneled Central Venous Catheters (Hickman), Peripherally Inserted Central Catheters (PICCs), and implantable PORTs are used to deliver systemic anticancer treatment via a central vein.

There are four types of Cental Venous Catheters (CVCs): Peripherally Inserted Central Catheters (PICCs), centrally inserted catheters (non-tunneled and tunneled), and implantable PORTS.

Nontunneled Central Venous Catheters (CVCs) are more commonly used, and inserted percutaneously into central veins (internal jugular, subclavian, or femoral vein), for short term use (usually less than 3 weeks, and account for the majority of central line-associated bloodstream infections.
Tunneled CVCs such as Hickman are implanted into internal jugular, subclavian, or femoral vein for long term use (weeks to months). They are associated with lower rate of infection than nontunneled CVCs and the dacron cuff inhibits migration of organisms into catheter tract when ingrown.
Implantable ports are inserted in the subclavian or internal jugular vein and tunneled beneath the skin, and the subcutaneous port is accessed with a noncoring needle. They are for long term use, and local catheter site care and dressing are not needed when not in use. They are associated with the lowest risk for central line-associated bloodstream infections.
Peripherally Inserted Central Catheter (PICC) is inserted percutaneously into basilic, brachial, or cephalic vein and enters the superior vena cava. They are usually for short to intermediate term use. PICC lines can usually be inserted at the bedside by a specially trained Registered Nurse. They can however be difficult to position in central vein and have the potential for occlusion.

The present study was conducted to compare the complication rates and costs of three central venous access devices, in order to establish acceptability, efficacy, and cost-effectiveness of the devices, for patients receiving systemic anticancer therapy.

This open-label, multicentre, randomized controlled trial (Cancer and Venous Access-CAVA) enrolled 1061 patients from 18 oncology centers in the UK. Eligible patients were over 18 years of age and had solid or hematological malignancy, and were receiving systemic anticancer therapy for 12 weeks or more. Enrolled patients assigned to use a central access device had four randomization options: Hickman versus PICC versus PORT (2:2:1), PICC versus Hickman (1:1), PORT versus Hickman (1:1), and PORT versus PICC (1:1). Randomization was done stratifying by centre, body mass index, type of cancer, device history, and treatment mode. The Primary outcome was complication rate (composite of infection, venous thrombosis, pulmonary embolus, inability to aspirate blood, mechanical failure, and other) assessed until device removal, withdrawal from study, or 1-year follow-up.

In the PORT versus Hickman comparison, PORTs were superior to Hickman with a complication rate of 29% versus 43% with Hickman catheters. PORTs were associated with lower rates of laboratory-confirmed bloodstream infection (6% versus 16%), exit site infection (4% versus 9%), were in place for a longer period (median 367 versus 165 days), were associated with a lower rate of complications per catheter week (0.02 versus 0.06), and a lower rate of removal due to complications (14% versus 32%), compared with Hickman catheters.

In the PORT versus PICC analysis, PORTs were again superior to PICCs, with a complication rate of 32% versus 47% respectively. PORTs were associated with lower rates of venous thrombosis (2% versus 11%; P=0.0024), mechanical failure (3% versus 11%), and were in place for a longer period of time (median 393 versus 119 days), and associated with a lower rate of complications per catheter week (0.05 versus 0.13), and a lower rate of removal due to complications (24% versus 38%).

In the PICC versus Hickman analysis, the complication rates observed with PICCs was 52% and was 49% with Hickman catheters. Non-inferiority of PICCs was not confirmed, potentially due to inadequate statistical power, even though the observed difference was less than 10%.

The authors based on this study concluded that for most patients receiving systemic anticancer therapy, PORTs are more effective and safer than both Hickman catheters and PICCs, and most patients receiving systemic anticancer therapy for solid tumors should therefore receive a PORT.

Central venous access devices for the delivery of systemic anticancer therapy (CAVA): a randomised controlled trial. Moss JG, Wu O, Bodenham AR, et al. Lancet 2021;398:403-415.

Duration of Extended Adjuvant Letrozole after Tamoxifen in Postmenopausal Women with Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

Approximately 75% of patients with breast cancer are Hormone Receptor (HR) – positive (Estrogen Receptor/Progesterone Receptor positive), and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues.

It has been well established that treatment with 5 years of endocrine therapy in early stage, HR-positive breast cancer, significantly reduces the risks of locoregional and distant recurrence, contralateral breast cancer, death from breast cancer, and therefore death from any cause. Extended adjuvant endocrine therapy with either Tamoxifen or an Aromatase Inhibitor (AI) beyond 5 years can further reduce breast cancer recurrence. This however can result in treatment related side effects. Therefore, when considering extended adjuvant endocrine therapy beyond 5 years, the potential benefits should be weighed against the associated risk with such therapy. The absolute benefit of continuing endocrine therapy after 5 years depends on the absolute risk of later recurrence, if patient’s receives no further therapy.

Third generation Aromatase Inhibitors (AIs), including Anastrozole, Exemestane and Letrozole, have demonstrated improved efficacy, when compared to Tamoxifen, for the adjuvant endocrine treatment of postmenopausal patients with HR-positive breast cancer. Randomized trials such as the Intergroup Exemestane Study have shown improvements in Disease Free Survival (DFS) among patients who after 2-3 years on Tamoxifen treatment switch to Exemestane for the remainder of a 5-year endocrine treatment period, with a modest improvement in Overall Survival (OS). Whether there is added benefit by extending Aromatase Inhibitor therapy beyond 5 years has remained controversial.

The present study was conducted to compare extended therapy with Letrozole for 5 years versus the standard duration of 2-3 years of Letrozole, in postmenopausal patients with breast cancer, who had already received 2-3 years of Tamoxifen. This multicentre, open-label, randomized, Phase III trial included 2056 postmenopausal women patients with Stage I-III operable, invasive, HR-positive breast cancer, who had received adjuvant Tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, and had no signs of recurrent disease. Patients were randomly assigned (1:1) to receive Letrozole 2.5 mg orally once a day for 2-3 years (control group; N=1030) or Letrozole 2.5 mg orally once a day for 5 years (extended group; N=1026). Approximately 41% of patients had node-positive disease, 21% had Grade 3 tumors, 6% had HER2-positive disease and 55% had prior chemotherapy. The median duration of treatment with adjuvant Tamoxifen was about 2.5 years. The Primary endpoint was invasive Disease Free Survival. Safety analysis was done for patients who received at least 1 month of study treatment. About 80% of patients in the control group and 63% in the extended treatment group completed treatment. The median duration of Letrozole treatment was 5.0 years in the extended treatment group and 2.4 years in the control group. About 16% of patients in the extended treatment group and 11.7% in the control group received bisphosphonate treatment respectively.

After a median follow-up of 11.7 years, the 12-year Disease Free Survival was 62% in the control group and 67% in the extended treatment group (HR=0.78; P=0.0064). This benefit was seen across all patient subgroups. The Overall Survival was also significantly improved at 12 years, and was 84% in the control group versus 88% in the extended treatment group (HR=0.77; P=0.036).

With regards to Adverse Events, there was a slightly higher incidence of arthralgia, myalgia and osteoporosis in the extended treatment group, but there was no significant difference observed between the groups in the incidence of Skeletal Related Events.

It was concluded from this landmark study that, in postmenopausal patients with breast cancer who received 2-3 years of Tamoxifen, extended treatment with 5 years of Letrozole resulted in a significant improvement in Disease Free Survival, compared with the standard 2-3 years of Letrozole. The authors added that sequential endocrine therapy with Tamoxifen for 2-3 years followed by Letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with Hormone Receptor-positive breast cancer.

Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial. Del Mastro L, Mansutti M, Bisagni G, et al. Lancet Oncology. Published: September 17, 2021. DOI: https://doi.org/10.1016/S1470-2045(21)00352-1

ASH 2021 Guidelines for Management of VTE in Patients with Cancer

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. There is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging.

American Society of Hematology (ASH) formed a multidisciplinary guideline panel and the guidelines summarized below are based on updated and original systematic reviews of evidence, conducted under the direction of the McMaster University GRADE Center with international collaborators. The main objective is to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer.

RECOMMENDATIONS
Primary prophylaxis for hospitalized medical patients with cancer.
♦ For patients without VTE, the panel suggests using thromboprophylaxis over no thromboprophylaxis and in whom pharmacologic thromboprophylaxis is used, the panel suggests using Low Molecular Weight Heparin (LMWH) over UnFractionated Heparin (UFH).
♦ For patients without VTE, the panel suggests using pharmacologic thromboprophylaxis over mechanical thromboprophylaxis or a combination of pharmacologic and mechanical thromboprophylaxis.
♦ For hospitalized medical patients with cancer, the ASH guideline panel suggests discontinuing thromboprophylaxis at the time of hospital discharge rather than continuing thromboprophylaxis beyond the discharge date.
Primary prophylaxis for patients with cancer undergoing surgery.
♦ For patients without VTE undergoing a surgical procedure at lower bleeding risk, the panel suggests using pharmacologic rather than mechanical thromboprophylaxis and for those undergoing a surgical procedure at high bleeding risk, the panel suggests using mechanical rather than pharmacologic thromboprophylaxis.
♦ For patients without VTE undergoing a surgical procedure at high risk for thrombosis, except in those at high risk of bleeding, the panel suggests using a combination of mechanical and pharmacologic thromboprophylaxis rather than mechanical prophylaxis alone or pharmacologic thromboprophylaxis alone.
♦ For all patients, the panel suggests using LMWH or Fondaparinux for thromboprophylaxis rather than UFH.
♦ The panel makes no recommendation on the use of Vitamin K Antagonists (VKAs) or Direct Oral AntiCoagulants (DOACs) for thromboprophylaxis, as there are no data.
♦ The panel suggests using postoperative thromboprophylaxis over preoperative thromboprophylaxis.
♦ For patients who have undergone a major abdominal/pelvic surgical procedure, the panel suggests continuing pharmacologic thromboprophylaxis, postdischarge rather than discontinuing at the time of hospital discharge.
Primary prophylaxis in ambulatory patients with cancer receiving systemic therapy.
♦ For patients at low and intermediate risk for thrombosis receiving systemic therapy, the panel recommends/suggests no thromboprophylaxis over parenteral thromboprophylaxis respectively. For patients at high risk, the panel suggests parenteral thromboprophylaxis (LMWH) over no thromboprophylaxis.
♦ The panel recommends no thromboprophylaxis over oral thromboprophylaxis with VKAs.
♦ For patients at low risk for thrombosis, the panel suggests no thromboprophylaxis over oral thromboprophylaxis with a DOAC (Apixaban or Rivaroxaban). For patients at intermediate risk, the panel suggests thromboprophylaxis with a DOAC (apixaban or rivaroxaban) or no thromboprophylaxis. For patients at high risk, the panel suggests thromboprophylaxis with a DOAC (Apixaban or Rivaroxaban) over no thromboprophylaxis.
♦ For patients with multiple myeloma receiving Lenalidomide, Thalidomide, or Pomalidomide-based regimens, the panel suggests using low-dose Aspirin or fixed low-dose VKAs or LMWH.
Primary prophylaxis for patients with cancer with Central Venous Catheter (CVC).
♦ The panel suggests not using parenteral or oral thromboprophylaxis.
Initial treatment (first week) for patients with active cancer and VTE.
♦ The panel suggests DOAC (Apixaban or Rivaroxaban) or LMWH be used for initial treatment of VTE.
♦ The panel recommends/suggests LMWH over UFH and Fondaparinux respectively, for initial treatment of VTE.
Short-term treatment for patients with active cancer (initial 3-6 months).
♦ The panel suggests DOACs (Apixaban, Edoxaban, or Rivaroxaban) over LMWH and VKAs, and LMWH over VKAs.
♦ For patients with incidental (unsuspected) Pulmonary Embolism (PE), or SubSegmental PE (SSPE), the panel suggests short-term anticoagulation treatment rather than observation.
♦ For patients with visceral/splanchnic vein thrombosis, the panel suggests treatment with short-term anticoagulation or observation.
♦ For patients with CVC-related VTE receiving anticoagulant treatment, the panel suggests keeping the CVC over removing the CVC.
♦ For patients with recurrent VTE despite receiving therapeutic LMWH, the panel suggests increasing the LMWH dose to a supratherapeutic level or continuing with a therapeutic dose.
♦ For patients with recurrent VTE despite anticoagulation treatment, the panel suggests not using an Inferior Vena Cava filter over using a filter.
Long-term treatment (>6 months) for patients with active cancer and VTE.
♦ The panel suggests long-term anticoagulation for secondary prophylaxis (> 6 months) rather than short-term treatment alone (3-6 months), and the panel suggests continuing indefinite anticoagulation over stopping after completion of a definitive period of anticoagulation.
♦ For patients requiring long-term anticoagulation (> 6 months), the panel suggests using DOACs or LMWH.

American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Lyman GH, Carrier M, Ay C, et al. Blood Adv 2021;5: 927–974.

Omitting Axillary Lymph Node Dissection in Patients with Clinically Positive Axillary Lymph Nodes Treated with Neoadjuvant Chemotherapy

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

Patients with locally advanced breast cancer with clinically positive axillary lymph nodes often receive chemotherapy in the neoadjuvant settings, and approximately 30-40% of patients achieve a pathological Complete Response (pCR), with eradication of disease in the axilla. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pCR following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS).

Previously published prospective trials have demonstrated that breast cancer patients with clinically positive axillary lymph nodes, who disease following neoadjuvant therapy is converted to clinically node negative disease, can safely undergo Sentinel Lymph Node Biopsy (SLNB) rather than axillary lymph node dissection, as the false negative rates are less than 10%, when 3 or more sentinel lymph nodes are retrieved. However, the rates of axillary lymph node recurrence in this population, has remained unclear. The purpose of this study was to evaluate axillary nodal recurrence rates in a consecutive cohort of breast cancer patients with clinically positive axillary lymph nodes, treated with neoadjuvant chemotherapy, who had negative disease following treatment, on Sentinel Lymph Node Biopsy.

This study included 769 patients with Stage II-III, biopsy-proven, node-positive breast cancer, of whom 610 patients were eligible for Sentinel Lymph Node Biopsy following neoadjuvant chemotherapy. Ninety one percent (N=555) converted to clinical node negative disease on physical examination, following neoadjuvant chemotherapy and 513 patients had 3 or more SLNs retrieved. Overall Axillary Lymph Node Dissection was avoided in 234 patients with 3 or more pathologically negative sentinel lymph nodes. The median patient age in this study cohort of 234 patients was 49 years. Median tumor size was 3 cm, 62% were HER2-positive, and 18% were triple negative. Majority of the patients (91%) received Doxorubicin-based neoadjuvant chemotherapy, 88% received adjuvant Radiotherapy (RT), and 70% of these patients also received nodal RT. The Primary outcome was the nodal recurrence rate among breast cancer patients with clinically positive axillary lymph nodes, treated with Sentinel Lymph Node Biopsy alone after neoadjuvant chemotherapy. Nodal recurrence was defined as a recurrence in the ipsilateral axillary, supraclavicular, or internal mammary nodal basins. Local recurrence was defined as an ipsilateral breast tumor recurrence. Distant failure included any distant metastases.

At a median follow up of 40 months, there was 1 axillary nodal recurrence, synchronous with local recurrence, in a patient who refused Radiation Therapy. Among patients who received Radiation Therapy (N=205), there were no nodal recurrences. The 5-year distant Recurrence Free Survival was 92.7%. The 5-year Overall Survival was 94.2%.

It was concluded from this study that in patients with clinically positive axillary lymph nodes, rendered clinically node negative with neoadjuvant chemotherapy, with 3 or more pathologically negative sentinel lymph nodes on Sentinel Lymph Node Biopsy alone, nodal recurrence rates were low without routine Axillary Lymph Node Dissection. These findings support surgical de-escalation by omitting Axillary Lymph Node Dissection in patients with clinically positive axillary lymph nodes, treated with neoadjuvant chemotherapy.

Nodal Recurrence in Patients with Node-Positive Breast Cancer Treated With Sentinel Node Biopsy Alone After Neoadjuvant Chemotherapy—A Rare Event. Barrio AV, Montagna G, Mamtani A, et al. JAMA Oncol. Published online October 7, 2021. doi:10.1001/jamaoncol.2021.4394