Does Biology or Therapy Define Oncology Outcomes?

Maurie Markman, MD

The debate over the relative impact on survival outcomes of therapy versus the inherent biology of an individual patient’s cancer remains one of the most controversial areas in all of cancer medicine. Even the results of well-designed and conducted phase III clinical trials cannot alter the opinion of many that observed equivalent survival outcomes between different therapeutic strategies are clinically irrelevant since “treatment in the study was not optimally applied.”

The continuing disagreement over the merits of aggressive primary surgical cytoreduction in advanced ovarian cancer is a striking example of this conundrum. Some vigorously argue that surgery that leaves a patient with no gross macroscopic cancer is a superior therapeutic approach compared with a neoadjuvant strategy, despite evidence-based phase III trial data to the contrary.¹ A recent report of a retrospective examination of the role of secondary cytoreduction for patients with low-grade serous ovarian cancer supports this view.2 The study revealed a rather striking improvement in time to subsequent disease progression (progression-free survival [PFS]) associated with the surgeon being able to remove all gross residual cancer compared with patients where gross residual cancer remained at the completion of surgery (median PFS, 60.3 months vs 10.7 months; P = .008).²

Although the authors concluded that “our results suggest a benefit to secondary cytoreductive surgery in patients with low-grade serous carcinoma,” it remains a completely open question as to whether the prolonged PFS is due principally or minimally to the skills of the surgeon versus the inherent biology of the cancer that permitted “successful complete cytoreduction.”²

Molecular Mutations in Context

Neither the role of anticancer therapy nor the fundamental impact of tumor biology on outcomes is in dispute; the question is the relative importance of these factors in a given clinical setting. This point was highlighted in a recent report of more 373,563 women diagnosed between 2004 and 2011 with invasive breast cancer who were included in the Surveillance, Epidemiology, and End Results (SEER) database.³

Controlling for tumor size (stage 1 cancers), estrogen receptor status, age at diagnosis, and income, the investigators examined the impact of various biological factors such as lymph node and distant metastases at diagnosis and the presence of triple-negative breast cancer in patients with different ethnic backgrounds. Of considerable interest, biological factors appeared to play a substantial role in the survival differences observed.

The obvious next question would be to inquire regarding the molecular characteristics that influence survival outcomes, with the subsequent goal of favorably impacting the biology of the malignancy. This might include increased surveillance of patients or the use of adjuvant therapies if there was reason to suspect the tumor had a relatively greater risk of recurring.

With the revolution in the ability of researchers to examine both germline variations/mutations and somatic abnormalities within the cancer, these questions can begin to be addressed.

For example, the potential impact on tumor recurrence of germline variations was explored among a group of 250 Korean patients with stage I non—small cell lung cancer, with the results subsequently verified in a second population of 308 individuals.⁴ The association with tumor recurrence based on the variants at one particular loci (rs1454694 on chromosome 4p34) was found to be particularly striking (HR = 2.81; P = 5.91 x 10-8).

A second recent report of 10-year survival among patients with ovarian cancer with BRCA1 (n = 1058) or BRCA2 (n = 438) mutations further supports the impact of the background germline on survival outcomes.⁵ The presence of either of these abnormalities was associated with superior short-term survival compared with nonmutation carriers; however, at 10-year follow up, patients with BRCA1 mutations actually had a worse overall survival than patients with ovarian cancer whose tumors did not harbor the mutation.

Turning to molecular abnormalities present within the tumor (rather than germline), investigators recently reported that individuals with gastrointestinal stromal tumors whose cancers possess a PDGFRA mutation experienced a superior relapse-free survival compared with patients with KIT mutations.⁶ However, patients with identical mutations were also found to have different risks of recurrence, presumably due to other relevant biological factors that, to date, remain poorly characterized.

As a final example of the impact of biology on outcome, investigators noted the very high risk of recurrence of papillary thyroid cancers in the presence of both a BRAF V600E and TERT promoter mutation compared with the absence of both abnormalities (68.6% vs 8.7%).⁷

We can anticipate that future research efforts will continue to more critically define the impact on survival of the inherent biology of a cancer versus the role of specific antineoplastic therapy.

References

1. Schorge JO, Clark RM, Lee SI, Penson RT. Primary debulking surgery for advanced ovarian cancer: are you a believer of a dissenter? [published online October 12, 2014] Gynecol Oncol. 2014;135(3):595-605.
2. Crane EK, Sun CC, Ramirez PT, et al. The role of secondary cytoreduction in low-grade serous ovarian cancer or peritoneal cancer [published online November 8, 2014]. Gynecol Oncol. 2015;136(1):25-29.
3. Iqbal J, Ginsburg O, Rochon PA, et al. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. JAMA. 2015;313(2):165-173.
4. Yoon KA, Jung MK, Lee D, et al. Genetic variations associated with postoperative recurrence in stage I non-small cell lung cancer [published online April 15, 2014]. Clin Cancer Res. 2014; 20(12):3272-3279.
5. Candido-dos-Reis FJ, Song H, Goode EL, et al. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer [published online November 14, 2014]. Clin Cancer Res. 2015;21(3):652-657.
6. Joensuu H, Rutkowski P, Nishida T, et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence [published online January 20, 2015]. J Clin Oncol. 2015;33(6):634-642.
7. Xing M, Liu R, Liu X, et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence [published online July 14, 2014]. J Clin Oncol. 2014;32(26):2718-2726