In this retrospective study of young patients (aged ≤35 years) with operable breast cancers, those with PABC have a similar outcome with regard to LRR, DM, and OS as those with non-PABC. One striking finding is that patients with PABC presented with more advanced T classification, N classification, and AJCC stage than similar patients with non-PABC. This suggests that the largest risk for patients with PABC is the delay of diagnosis of their disease.
PABC is a relatively rare entity that presents unique challenges for both diagnosis and management. Prior reports have suggested that approximately 10% of breast cancers diagnosed in patients aged ≤40 years were diagnosed during pregnancy.2
In this study, 15.6% of breast cancers diagnosed in patients aged ≤35 years were considered pregnancy-associated; overall, 7.6% were diagnosed during pregnancy and 7.9% within 1 year after delivery. Although the rate of this study is generally consistent with published reports, the increase over the expected rate (15.6% vs 10%) may be attributable to the finding that the M. D. Anderson Cancer Center has conducted the only prospective trial for PABC in North America.9
Our data suggest that the patients who develop PABC may not be promptly diagnosed and evaluated. Prioritization of the pregnancy and other psychosocial issues may play a role in this. In addition, normal variations in breast density and potential benign conditions that are more common during pregnancy, including engorgement and mastitis, can both mimic and mask the symptoms of breast cancer.12,13
Although the current study does not address the issue of false-negative results in screening these women, it does suggest that women who are pregnant or within 1 year of delivery who develop breast cancer are diagnosed with more advanced stage disease than those who have not had an associated pregnancy. This suggests that physicians who care for these patients should be more aggressive in the workup and diagnostic evaluation of breast symptoms in this population. Although routine mammography is not indicated given the potential radiation exposure to the fetus, use of mammography with appropriate fetal shielding has been safely integrated into the evaluation of patients on prospective trials of PABC.9
In addition, ultrasound is an appropriate diagnostic study and may provide valuable information with no risk to the unborn child.
Once diagnosed, young patients (aged ≤35 years) with PABC have similar outcomes as young patients with non-PABC, both overall and stage-by-stage, which are relatively poor compared with historical breast cancer series comprising all age groups. This suggests that the poorer outcomes are largely a result of the young age of the patients and not the pregnancy itself. This is consistent with prior reports in the literature. Zemlickis et al reviewed the cases of 118 women diagnosed with breast cancer during pregnancy and 269 nonpregnant controls, and they found that the women who presented while pregnant had more advanced disease but no difference in outcome, with a 10-year OS of 40% for patients with PABC and 48% for those with non-PABC.5
Other retrospective studies demonstrated similar results with regard to overall survival. Ezzat et al reported a 7-year overall survival rate of 57% for patients with PABC versus 61% for patients with non-PABC.8
Bonnier et al reported a 5-year overall survival of 61% for PABC versus 75% for non-PABC.4
Middleton et al evaluated the histopathology of 39 patients with PABC and found that the pathologic findings correlated with those described in young cohorts, having poor prognostic and histologic features; there were no unique histopathologic features identified within the PABC group specifically.14
The current study did find that patients with PABC who were diagnosed during pregnancy had a statistically significant increased rate of LVSI compared with patients diagnosed in the 1 year after delivery; however, their outcomes were statistically similar. In aggregate, these data suggest that patients with PABC do not have an inferior outcome when diagnosed either during pregnancy or within 1 year after delivery; nonetheless, significant improvements need to be made in the management of all breast cancers in this group of young patients.
Limitations in our understanding of PABC, from the perspective of optimal management of both the mother and fetus, are currently being addressed with prospective IRB-approved trials. The outcome of pregnant patients and their fetuses treated with systemic chemotherapy including 5-fluorouracil, doxorubicin, and cyclophosphamide is currently being addressed with a large, single-arm, institutional study at the M. D. Anderson Cancer Center. Current data suggest that this regimen is well tolerated, with minimal toxicity to the unborn child, and with maternal outcomes consistent with published reports.9
Although these data are preliminary, they suggest that women with PABC can be well managed with neoadjuvant chemotherapy and that termination is not necessary to optimize the outcomes of either mother or child. Further follow-up is needed to characterize any potential long-term sequelae to this strategy for both the mothers and children, including comprehensive medical assessments as the children enter their reproductive years.
The similar outcomes for young women with PABC and those with non-PABC demonstrated in this study are intriguing; however, there are inherent limitations to the current investigation. Given that the data were collected retrospectively, there are limitations in the information available as well as potential biases that may have contributed to treatment decisions and impacted outcomes. We have attempted to minimize these differences by excluding patients with inflammatory breast cancer (n = 29), who are treated at our institution with an aggressive treatment schema that is different from the standard therapy, and likely represent a cohort of patients with different underlying biology.15–17
It should be noted that clinical difficulty in discerning skin involvement in pregnant patients secondary to breast engorgement or pregnancy-related breast skin changes would be expected to lead to an over-representation of false-positive T4 staging. These data are difficult to discern retrospectively. However, this bias, if present, would make the differences in stage at presentation less significant rather than more significant and further support the conclusions as reported. In addition, because the scope of this review extends before routine metastatic screening with computed tomography, we have excluded those patients (n = 26) who developed metastatic disease within 6 months of diagnosis, because we believe that these likely represent patients with underappreciated metastatic disease at presentation. For the remaining patient population, we have attempted to elucidate any differences by comparing the patient groups and indicated discrepancies when they are statistically significant. Furthermore, this study extends for several decades during which treatment philosophies, techniques, and technologies have evolved. We have analyzed outcome by decade and found no statistically significant differences; although treatment regimens may have changed, there is no evidence that this historical evolution has contributed to our observations and conclusions. Although our data are strengthened by a large patient population, these findings should be viewed as hypothesis-generating. The lack of a statistically significant correlation between the diagnosis of PABC and a worse outcome does not necessarily preclude a true association. Furthermore, it is difficult to determine whether the concurrent pregnancy, with its hormonal and physiologic effects, influences the stage and aggressivity of the underlying malignancy. Our study does, however, provide hypothesis-generating data that among young women with breast cancers of similar stage and treatment, differing predominantly by pregnancy association, outcomes are statistically similar; notably, these outcomes are consistently worse than those for older women with similar disease and treatment. Additional studies with increased power will be necessary to fully elucidate the interaction of gestational hormonal influences with breast cancer pathogenesis and to attempt to separate these from interactions that occur secondary to young age itself.
Our current study highlights the importance of adequate diagnosis and treatment in the management of PABC. Pregnancy itself does not impart a worse prognosis; however, pregnancy does mask symptoms and hinder diagnosis. The education of patients and primary care physicians that breast symptoms during and immediately after pregnancy should be fully investigated will help hasten diagnosis and maximize treatment. Of those patients who were diagnosed during pregnancy, there is a trend toward improved outcome with any treatment given. Those patients in whom diagnosis was delayed or treatment deferred until after delivery had an inferior survival compared with those who received immediate diagnosis followed by chemotherapy, surgery, or therapeutic abortion (followed by immediate treatment). Overall, breast cancer in young patients (aged ≤35 years) is an aggressive disease; improvement in comprehensive multidisciplinary management is needed in all patients, but especially in those patients whose cancers are associated with pregnancy. Balancing the health of mother and child is also paramount; new evidence suggests that both can be prioritized and successful outcomes managed for both.