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Summary in Thirty Seconds
Starting treatment immediately after being diagnosed with cancer seems logical; however, doing so before having specific biomarker testing might be unwise because molecular testing can identify important therapeutic targets.
Research suggests it is safe for patients with cancer such as NSCLC to wait for genetic test results before starting chemotherapy, and delays in receiving biomarker test results may lead some patients to start treatment before receiving results.
Survival rates appear more affected by treatment delays in early-stage cancers, particularly when delaying surgery and sometimes with delays in radiotherapy or chemotherapy.
Initiating chemotherapy before understanding the oncogenic variations that may be driving cancer has risks, including that chemotherapy can induce new mutations, including genetic/chromosomal rearrangements making targeted treatment less effective.
For most cancers, the benefits outweigh the costs of waiting one-to-three weeks to get biomarker test results directing treatment to particular actionable targets. Enduring such a wait takes open and honest communication with healthcare providers regarding the value of waiting for biomarker test results.
The Urge to Act Now
The American Cancer Society estimates that 5,250 people were diagnosed each day with cancer in 2022 (1,918,300 annual diagnoses).[1] For each of these people, a multitude of emotions comes with this news, and with these feelings often, understandably, comes the urge to “do something now.”[2] Important questions related to this impulse, however, are what to do, how long to wait to do it, and what are the costs/benefits of waiting, particularly for diagnostic testing before starting treatment.
Why Wait to Start Cancer Treatment?
It might seem logical to start treatment as soon as possible post-diagnosis. But a cancer diagnosis identifies the general problem rather than the specific cause. Thus, beginning cancer treatment before having specific biomarker testing done might be like putting a cast on a leg before getting an x-ray or buying glasses before having an eye exam. Molecular testing is crucial when indicated since important therapeutic targets might be potentially missed if no molecular analyses were performed.[3] A 2021 JAMA Oncology study found that nearly 80% of people with cancer had a potentially actionable genomic alteration,[4] so biomarker testing is vital for finding the right treatment for the specific cancer cause.
Is Waiting to Start Treatment Safe? (NSCLC Example)
A study of 303 metastatic NSCLC patients without driver mutations found that a longer interval between diagnosis and the start of chemotherapy had no impact on prognosis. This result led the authors to conclude that it was safe for patients and their physicians to wait for genetic test results before starting chemotherapy in this patient population.[5] Notably, delays in receiving biomarker test results in one study led more than one in five patients with metastatic NSCLC to start treatment before receiving the test results.[6] This suggests the possibility of poor communication between patients and healthcare providers about the benefits of waiting for NGS results. Furthermore, waiting may not only be safe, but beneficial. A study of over 750 patients with stage IV EGFR NSCLC revealed that those waiting to get biomarker test results before starting treatment had better long-term survival and time-to-next-treatment outcomes.[7]
Cost of Waiting
A review of the National Cancer Database evaluated 3,672,561 people with early-stage breast, prostate, lung, colorectal, renal, and pancreatic cancers from 2004-2013.[8] The median time to initiate treatment post-diagnosis was 27 days. This study found that time to treatment initiation has increased over the years evaluated in the study, and for each week of delay, the risk of mortality rose 1.2 to 3.2% for early-stage breast, lung, renal, and pancreatic cancers. The authors emphasized that survival rates are more affected by treatment delays in early-stage cancers, which may be related to the lower use of systemic therapies (and more frequent use of surgery) in early-stage cancers. A meta-analysis reviewing 272,681 patients across 34 studies for seven major tumor types[9] found that delaying surgery was related to an increased risk of mortality (a 6-8% increase in the chance of death at 4 weeks); radiotherapy delays increased mortality for specific cancer types/stages; and delaying systemic therapy showed variable results depending on the cancer type. Importantly in these two huge studies, systemic treatments were chemotherapy rather than immunotherapy or targeted therapies. A study[10] of 28,732 U.S. patients with NSCLC found that a diagnosis-to-treatment interval of 35 days or less was associated with improved survival rates across stages. But delays of more than 8 weeks for stage I, II, or III NSCLC patients from diagnosis to treatment led to disease progression in 31% of patients.[11]
Cost of Not Waiting and Benefits of Waiting (NSCLC Example)
Initiating chemotherapy before understanding the oncogenic variations that may be driving cancer has risks, particularly in the case of advanced NSCLC.[12] A concern is that chemotherapy can induce new mutations, including genetic/chromosomal rearrangements.[13],[14] Such intratumor heterogeneity has been linked to greater resistance to targeted therapies leading to poorer treatment outcomes.[15],[16]
Because of such findings, international and national guidelines now consistently recommend testing for oncogenic driver alterations in all patients with advanced lung cancer prior to the start of systemic treatment.[17] Heigener et al.[18] broaden this by recommending complete pathologic and biologic typing of NSCLC tumors as mandatory to guide first-line treatment using next-generation sequencing (NGS) to identify molecular targetable alterations. And a panel of experts recommends that all patients with nonsquamous NSCLC, regardless of stage, should undergo comprehensive reflex biomarker testing at diagnosis with targeted NGS.[19] Clinical outcomes (i.e., survival) have been demonstrably improved after targeted therapy informed by biomarker testing,[20] with one retrospective study of almost 3,500 patients showing significantly better outcomes in those receiving targeted therapies compared to chemotherapy.[21]
How Long Do NGS Test Results Take?
JAMA estimates that NGS tests take 2-3 weeks to return.[22] A study of over 450 patients found the turnaround time from blood draw to returned results in plasma NGS had a median of 9 days.[23] Another study looked at plasma-based NGS testing and found that 85% of patients with NSCLC had test results available at their first oncology visit, compared to less than 10% who used diagnostic biopsy results. Furthermore, the time to initiate treatment was cut almost in half for those with plasma-based NGS testing.[24] An ASCO survey of US oncologists[25] concluded that delays in biomarker test results affect treatment decisions. This led to the recommendation that healthcare providers be informed about when it is safe and appropriate to wait for the start of treatment until biomarker test results are known.
The Benefits Outweigh the Costs
Study and clinical data show that for most cancers, waiting one-to-three weeks to get biomarker test results directing treatment to particular actionable targets is worth it. For patients who wish to act immediately, enduring such a wait takes open and honest communication with healthcare providers. Importantly, there are a small number of cancers where waiting for NGS may be less indicated because the likelihood of identifying a targetable mutation is low,[26] or the disease is in its early stage and effective forms of standard treatment are well-documented.[27] It is important to educate people with cancer as well as their healthcare providers regarding the value of waiting for biomarker test results.[28]
We wait to get a vision test before buying glasses, and cancer is magnitudes more serious than myopia. When given the diagnosis of cancer, the reflexive response is to do something now. While in a small number of cases, acting quickly is appropriate, in most cases, more effective treatments come for those who wait.
[1] CA Cancer J Clin. 2022; 72:7–33 [2] Am Psychol. 2015 Feb-Mar; 70(2):105–118 [3] CA Cancer J Clin. 2019 Jul-Aug; 69(4):305–343 [4] JAMA Oncol. 2021; 7(4):525-533 [5] Oncol Res Treat. 2021; 44:12–18 [6] JCO Precision Oncology 2018; 2:1-11 [7] J of the National Comprehensive Cancer Network 20, 3.5 [8] PLoS ONE 14(3): e0213209 [9] BMJ 2020; 371:m4087 [10] Radiother Oncol 2015; 115(2):257–63 [11] Int J Radiat Oncol Biol Phys. 2011; 79 (2):466-472 [12] Nature Reviews Clinical Oncology. 2019; 16:341–355 [13] J of Molecular Medicine. 2020 98:161–177 [14] Cancer Chemotherapy and Pharmacology. 2012; 69:289–299 [15] J of Hematology & Oncology. 2019; 12:134 [16] Nat. Rev. Clin. Oncol. 2017; 15(2):81–94 [17] Lung Cancer. 2022, March; 165:34-42 [18] Clin Cancer Res.2019; 25(16):4881–4887 [19] Curr. Oncol. 2020; 27(6):321-329 [20] Expert Review of Anticancer Therapy. 2022; 22(9):927-937 [21] Cancer Medicine. 2022; 11(1):86–93 [22] JAMA Oncol. 2019;5(7):1076 [23] JCO Precision Oncology. 2020; 4:1098-1108 [24] JTO Clinical and Research Reports Vol. 3 No. 4: 100301 [25] J of Clinical Oncology. 2021; 39(15_suppl): 9067-9067 [26] JAMA Oncol. 2019; 5(7):1076 [27] J. E.Clin.M.2020; 25:100487 [28] Educating Patients About the Need to Wait for Biomarker Test Results - Journal of Oncology Navigation & Survivorship (jons-online.com)