The goal of effective adjuvant therapy is to increase overall survival. It has been suggested cynically that all we need to accomplish, actually, is to delay recurrence until after the time the patients die from another cause. However, patients want to hear from us that “it’s never coming back,” and that is what we treating oncologists hope for, as well.

There are currently no validated measures of the effectiveness of chemotherapy other than to wait for clinical evidence of recurrence. Recurrence in a visceral site almost always means that the disease cannot be cured.

Response to Neoadjuvant Therapy

Neoadjuvant therapy has a number of clinical advantages and utilities. Chemotherapy before surgery permits the initiation of systemic therapy earlier in the disease, although there is no certain evidence that earlier therapy is more effective than traditional adjuvant therapy.

For some patients, it appears that a pathologic complete response portends a longer disease-free survival compared with patients who have residual disease. Early treatment often results in a reduction in the extent of surgery required for primary therapy, although this appears not to predict overall survival accurately.

Finally, neoadjuvant chemotherapy functions as a chemosensitivity assay demonstrating local effectiveness of chemotherapy on the primary tumor. Response, however, appears not to relate directly to the duration of survival or to a reduction in the chance of recurrence.

Limitations of Pathologic Response

In a clinical trials setting, the question we wish to answer is one of competitive efficiency and effectiveness: Is treatment A more effective than treatment B? Adjuvant trials unfortunately take a long time to complete, and they are very expensive. In addition, validation of a biomarker is a circular process in which we first need to observe that a putative marker declines with effective therapy and is associated subsequently with increased survival as the ultimate endpoint.

Disappointingly—as reported by Cortazar and colleagues in The Lancet and reviewed in this issue of The ASCO Post—pathologic complete response in the pooled Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) analysis at the level of clinical trials showed little association with effective treatment in either event-free or overall survival.¹ Pathologic complete response is thus a proximate marker of tumor response, but it appears to be neither the most informative nor a valid marker of overall survival.

Pathologic complete response tells us only that the tumor in the organ of origin or in regional lymph nodes has responded to treatment. It does not tell us about the status of micrometastases or their response to therapy.

We want to conclude that if there is a pathologic complete response, there must be an overall complete response and an accompanying increase in overall survival, but this may not be so. Assessing pathologic response at the organ level appears to be too crude to indicate survival duration reliably.

Thus, pathologic complete response is a 19th and 20th century concept. We need a 21st century concept of response accompanied by an insightful genomic or biological marker.

Other Potential Biomarkers

The ideal biomarker of treatment responsiveness would show that all micrometastases have either disappeared or are quiescent and will not recur. Assessing the response of dormant micrometastases is our great and most pressing clinical trials need, but we don’t yet know how to do that. A marker with such utility remains to be identified.

Several other markers have been proposed as potential surrogates for response duration. Circulating tumor cells do not appear to accomplish the task, however, and validation studies have failed to prove their ultimate clinical utility in the adjuvant setting.^2,3

Circulating tumor DNA holds promise as a predictor of event-free or overall survival, but no validation studies have been conducted.⁴ Circulating tumor DNA is detectable in more than 75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers.

In patients with localized tumors, circulating tumor DNA can be detected in up to 70% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma.⁵ Because circulating tumor DNA is often present in patients without detectable circulating tumor cells, these two biomarkers appear to be distinct entities. How validation studies of these promising markers should be designed and conducted remains an elusive clinical challenge.

Ultimate Challenge

Our challenge is not simply in using a surrogate marker of response. The reality is that we can no longer afford the luxury of using either pathologic response or overall survival as the outcome standard for our clinical trials. We need to decrease the cost of conducting adjuvant treatment trials for patients with malignancy, and we need to reduce the time required to identify new and effective agents. We also need to exercise great caution to avoid the type II error in rejecting new and effective therapies. Designing such trials will require both ingenuity and creativity.

With our increasing knowledge of the human genome and continuing identification of mutational markers associated with treatment response, we can begin to identify improved intermediate indicators that will make biomarker response a realistic standard in the near future. We will need to incorporate that knowledge into innovative and creative designs of new clinical trials that evaluate our cancer therapies to achieve these laudable and necessary goals. ■

Disclosure: Dr. Vogel reported no potential conflicts of interest.

References

1. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. February 13, 2014 (early release online).

2. Cristofanilli M, Budd T, Ellis, MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004.

3. Bidard F-C, Peeters DJ, Fehm T, et al: Clinical validity of circulating tumour cells in patients with metastatic breast cancer: A pooled analysis of individual patient data. Lancet Oncol. March 11, 2014 (early release online).

4. Krebs MG, Metcalf RL, Carter L, et al: Molecular analysis of circulating tumour cells—biology and biomarkers. Nat Rev Clin Oncol 11:129-144, 2014.

5. Bettegowda C, Sausen M, Leary RJ, et al: Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. February 19, 2014 (early release online).

Dr. Vogel is Director, Breast Medical Oncology/Research, Geisinger Health System, Danville, Pennsylavnia.